CN116693680A - Antibodies specifically recognizing pseudomonas PSL and uses thereof - Google Patents

Antibodies specifically recognizing pseudomonas PSL and uses thereof Download PDF

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CN116693680A
CN116693680A CN202310601324.XA CN202310601324A CN116693680A CN 116693680 A CN116693680 A CN 116693680A CN 202310601324 A CN202310601324 A CN 202310601324A CN 116693680 A CN116693680 A CN 116693680A
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李忠
于茂荣
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Beijing Solobio Genetechnology Co Ltd
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Abstract

The application provides an antibody specifically recognizing pseudomonas Psl, including an antigen binding fragment thereof, and also provides a preparation method and application thereof.

Description

Antibodies specifically recognizing pseudomonas PSL and uses thereof
The contents of the sequence Listing (text name: PSL antibody seqlist-division China office 20230411.Xml, recording date: 2023.04.11, size: 271 KB) submitted below are incorporated herein by reference in their entirety.
Technical Field
The present application relates to antibodies specifically recognizing pseudomonas aeruginosa (Pseudomonas aeruginosa, PA) Psl, methods of making and uses thereof, including methods of treating and preventing pseudomonas infection therewith.
Background
Pseudomonas aeruginosa is an obligate aerobic gram-negative bacillus that is widely found in nature. Although it is generally low in pathogenicity, it is a pathogen that causes opportunistic infections that often occur in patients with various underlying diseases such as cancer, diabetes, immunodeficiency, and the like and who take drugs with immunosuppressive effects. Pseudomonas aeruginosa infection is prone to occur in patients with disrupted skin mucosa, and patients with chronic structural lung disease (e.g., chronic obstructive pulmonary disease or cystic fibrosis) are also at considerable risk of infection. Pseudomonas aeruginosa causes pneumonia, urinary tract infection, septicemia and the like, and often causes serious consequences. Up to 10% of nosocomial infections are caused by pseudomonas aeruginosa, with mortality rates approaching 40% in pseudomonas aeruginosa bacteremia patients. Clinically, pseudomonas aeruginosa infection is considered one of the most difficult infections to treat, not only because pseudomonas aeruginosa itself has low sensitivity to existing antibiotics, but also because it is easily resistant to multiple antibiotics. Thus, strategies for developing antibiotics have limited advantages in combating pseudomonas aeruginosa infection.
Pseudomonas aeruginosa is one of the major causes of hospital acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. One key component of the pseudomonas aeruginosa biofilm matrix is the polysaccharide Psl, which is produced by the protein encoded by the polysaccharide synthesis site. The Psl may be either dissociated outside the cell or bound to the cell surface. The structure of the extracellular Psl consists of pentasaccharide repeat units of D-mannose, L-rhamnose and D-glucose. Since Psl has both structural and protective functions during biofilm formation, and is also known to protect biofilms from antibiotics (by chemical binding) and the immune system (by an unknown mechanism), it may be an ideal target for new therapeutic options (Ray va et al anti-Psl Targeting of Pseudomonas aeruginosa Biofilms for Neutrophil-Mediated dis-ruption. Sci rep.2017). Human monoclonal antibodies (mAbs) targeting Psl, such as Wapr-001, wapr-016, cap-003 or derivatives thereof, psl0096, are described in (DiGiandomenico, A.et al.identification of broadly protective human antibodies to Pseudomonas aeruginosa exopolysaccharide Psl by phenotypic screening J Exp Med 209,1273-1287;Valerie A.Ray,et al,Anti-Psl targeting of Pseudomonas aeruginosa biofilms for neutrophil mediated disruption, scientific Reports7, article number:16065 (2017)).
The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety.
Summary of the application
The present application provides an isolated antibody or antigen binding fragment that specifically binds to pseudomonas Psl, and methods for the prevention and treatment of pseudomonas infection.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: v (V) H The V is H Comprising: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, or a variant thereof comprising up to 3 amino acid substitutions; a HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 14-15, 17-23, or a variant thereof comprising up to 3 amino acid substitutions; and a HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs 25-26, 28-34, or a variant thereof comprising up to 3 amino acid substitutions.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs 38-39, 41-49, or a variant thereof comprising up to 3 amino acid substitutions; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 52-53, 55-61, or a variant thereof comprising up to 3 amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs 63-64, 66-68, 70-75, or a variant thereof comprising up to 3 amino acid substitutions.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: v (V) H The saidV H Comprising: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, or a variant thereof comprising up to 3 amino acid substitutions; a HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 14-15, 17-23, or a variant thereof comprising up to 3 amino acid substitutions; and a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34, or a variant thereof comprising up to 3 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs 38-39, 41-49, or a variant thereof comprising up to 3 amino acid substitutions; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 52-53, 55-61, or a variant thereof comprising up to 3 amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs 63-64, 66-68, 70-75, or a variant thereof comprising up to 3 amino acid substitutions.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (ii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (iv) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; or in HC-CDRsV with up to 5 amino acid substitutions H Variants; (v) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (vi) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (vii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (viii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (ix) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (x) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; or (xi) V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 64, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iv) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (v) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vi) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71, or in LCV comprising up to 5 amino acid substitutions in the CDRs L Variants; (viii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ix) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (x) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (xi) V L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, one comprising the amino acid sequenceHC-CDR2 of SEQ ID NO. 15, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 64, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iv) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (v) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 68LC-CDR3, or V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vi) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (viii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ix) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (x) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (xi) V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: v (V) H The V is H Comprising a V having the amino acid sequence of any one of SEQ ID NOs 80-81, 83-90, 159 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence of any one of SEQ ID NOs 92-93, 95-97, 99-104 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In one aspect, the application provides an isolated antibody or antigen-binding sheet that specifically binds to Pseudomonas PslA segment, comprising: v (V) H The V is H Comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90, 159, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90, 159; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97, 99-104, or comprising variant sequences having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97, 99-104.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: v comprising the amino acid sequence of any one of SEQ ID NOs 80-81, 83-90, 159 H And V comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97, 99-104 L 。
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V comprising the amino acid sequence SEQ ID NO 80 H And V comprising the amino acid sequence SEQ ID NO. 92 L The method comprises the steps of carrying out a first treatment on the surface of the (ii) V comprising the amino acid sequence SEQ ID NO. 81 H And V comprising the amino acid sequence SEQ ID NO. 93 L The method comprises the steps of carrying out a first treatment on the surface of the (iii) V comprising the amino acid sequence SEQ ID NO. 83 H And V comprising the amino acid sequence SEQ ID NO 95 L The method comprises the steps of carrying out a first treatment on the surface of the (iv) V comprising the amino acid sequence SEQ ID NO 84 H And V comprising the amino acid sequence SEQ ID NO. 96 L The method comprises the steps of carrying out a first treatment on the surface of the (v) V comprising the amino acid sequence SEQ ID NO. 85 H And V comprising the amino acid sequence SEQ ID NO 97 L The method comprises the steps of carrying out a first treatment on the surface of the (vi) V comprising the amino acid sequence SEQ ID NO 86 H And V comprising the amino acid sequence SEQ ID NO 99 L The method comprises the steps of carrying out a first treatment on the surface of the (vii) V comprising the amino acid sequence SEQ ID NO. 81 H And V comprising the amino acid sequence SEQ ID NO. 100 L The method comprises the steps of carrying out a first treatment on the surface of the (viii) V comprising the amino acid sequence SEQ ID NO. 87 H And V comprising the amino acid sequence SEQ ID NO. 101 L The method comprises the steps of carrying out a first treatment on the surface of the (ix) V comprising the amino acid sequence SEQ ID NO 88 H And comprises an amino acid sequenceV of SEQ ID NO. 102 L The method comprises the steps of carrying out a first treatment on the surface of the (x) V comprising the amino acid sequence SEQ ID NO. 89 H And V comprising the amino acid sequence SEQ ID NO. 103 L The method comprises the steps of carrying out a first treatment on the surface of the (xi) V comprising the amino acid sequence SEQ ID NO. 90 H And V comprising the amino acid sequence SEQ ID NO 104 L The method comprises the steps of carrying out a first treatment on the surface of the Or (xii) V comprising the amino acid sequence SEQ ID NO 159 H And V comprising the amino acid sequence SEQ ID NO 95 L 。
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising IHSVH (SEQ ID NO: 4), or a variant thereof comprising up to 3 amino acid substitutions; one HC-CDR2 comprising TIISSGTTTTYAQSFQD (SEQ ID NO: 16), or a variant thereof comprising up to 3 amino acid substitutions; and an HC-CDR3 comprising X 1 X 2 X 3 X 4 (SEQ ID NO: 189), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 D, Y or N, X 2 Is G or A, X 3 Is D or T, X 4 S, A or T;
light chain variable domain (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising
RASQGISSWLA (SEQ ID NO: 40), or a variant thereof comprising up to 3 amino acid substitutions; an LC-CDR2 comprising HASTLES (SEQ ID NO: 54), or a variant thereof comprising up to 3 amino acid substitutions; and one
LC-CDR3 comprising LQAX 1 SLPTH (SEQ ID NO: 158), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, D, Y, F, P, G, K, H, A, C, E, Q, R, S, T, V, W or L.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising IHSVH (SEQ ID NO: 4), a HC-CDR2 comprising TIISSGTTTTYAQSFQD (SEQ ID NO: 16) and a polypeptide comprising a polypeptide selected from the group consisting of SEQ ID NO:27, SEQ ID NO:35,HC-CDR3 of the amino acid sequence in groups 165-169 of SEQ ID NOs; light chain variable domain (V L ) The V is L Comprising the following steps: one comprises
RASQGISSWLA (SEQ ID NO: 40), a LC-CDR2 comprising HASLTLES (SEQ ID NO: 54) and a LC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NOs:76-78, SEQ ID NOs: 199-212.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC comprising the amino acid sequence SEQ ID NO. 40-CDR1, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 54, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 76, or V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (iv) V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94; (ii) V (V) H The V is H Comprising an amino acid sequence of any of amino acids SEQ ID SEQ ID NOs:105-110, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any of amino acid sequences of SEQ ID NOs:105-110; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94; (iii) V (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising the amino acid sequenceThe variant sequence of SEQ ID NO. 82 having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOS.111-127, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of the amino acid sequences of SEQ ID NOS.111-127; (iv) V (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 113, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 113; (v) V (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 123, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 123; or (vi) V H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 116, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 116.
In one aspect, the application provides an isolated anti-specifically binding to Pseudomonas PslA body or antigen binding fragment comprising: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising SSGDYWG (SEQ ID NO: 1), or a variant thereof comprising up to 3 amino acid substitutions; one comprises
SIHNX 1 GSTYYNPSLKG (SEQ ID NO: 213), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 S, K or Q; and one containing QFGSETYYX 1 GIX 2 HC-CDR3 of P (SEQ ID NO: 190), or variants thereof comprising up to 3 amino acid substitutions, wherein X 1 N, S, V, T or P, X 2 D, Y, C, H, S, R, A, E, G, K, W, V or Q; light chain variable domain (V L ) The V is L Comprising the following steps: comprising RSSQSLLHSX 1 Light chain complementarity determining region (LC-CDR) 1 of GYNYLD (SEQ ID NO: 184), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, A, V, F, R, G, H, Q, W or P; an LC-CDR2 comprising lgsnas (SEQ ID NO: 51), or a variant thereof comprising up to 3 amino acid substitutions; and one containing MQALQTPX 1 LC-CDR3 of T (SEQ ID NO: 214), wherein X 1 Is R or Y, or a variant thereof comprising up to 3 amino acid substitutions.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising SSGDYWG (SEQ ID NO: 1); an HC-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO 13, SEQ ID NOs 163-164; and a HC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:24, SEQ ID NO:36, SEQ ID NOs:170-183, SEQ ID NOs: 185-188. Light chain variable domain (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 37, SEQ ID NO. 50, SEQ ID NOs 191-198; an LC-CDR2 comprising LGSNRAS (SEQ ID NO: 51); and an LC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:62, SEQ ID NO:69.
In one aspect, the present application providesAn isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (iv) V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; or comprises up to 5 amino acid substitutions in the HC-CDRsV of (2) H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In one aspect, the application provides an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl, comprising: (i) V (V) H The V is H Comprising the amino acid sequence SEQ ID NOs:79, or comprising variant sequences having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology to the amino acid sequence SEQ ID NOs: 79; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91; (ii) V (V) H The V is H A variant sequence comprising any one of SEQ ID NOs 128-139, 149-151, 154-155, or comprising at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of SEQ ID NOs 128-139, 149-151, 154-155; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91; (iii) V (V) H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 140-148, or comprising at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96% >, a sequence of amino acids identical to any one of the amino acid sequences of SEQ ID NOs 140-148,97%, 98%, or 99%) sequence homology; (iv) V (V) H The V is H A variant sequence comprising any one of SEQ ID No. 132, SEQ ID No. 149, SEQ ID nos. 152-153, SEQ ID nos. 156-157, or comprising at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of SEQ ID No. 132, SEQ ID No. 149, SEQ ID nos. 152-153, SEQ ID nos. 156-157; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143; or (V) V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 98, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 98.
In some embodiments, an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl is provided that competes with any of the antibodies or antigen-binding fragments described above that specifically bind to pseudomonas Psl. In some embodiments, an isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl is provided that binds to the same epitope as any of the antibodies or antigen-binding fragments that specifically bind to pseudomonas Psl described above.
In some embodiments, any of the isolated antibodies or antigen-binding fragments that specifically bind pseudomonas Psl described above comprises an Fc fragment. In some embodiments, the isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl is a full length IgG antibody. In some embodiments, the isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl is a full length IgG1 or IgG4 antibody. In some embodiments, the isolated antibody or antigen-binding fragment that specifically binds to pseudomonas Psl is chimeric, fully human, or humanized. In some embodiments, the isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl is an antigen-binding fragment selected from the group consisting of Fab, fab ', F (ab) '2, fab ' -SH, single chain antibody (scFv), fv fragment, dAb, fd, or diabody (diabody).
In some embodiments, an isolated nucleic acid molecule is provided that encodes any of the antibodies or antigen-binding fragments described above that specifically bind to pseudomonas Psl. In some embodiments, a vector is provided comprising any of the nucleic acid molecules described above. In some embodiments, a host cell is provided comprising any of the isolated antibodies or antigen-binding fragments, any of the nucleic acid molecules, or any of the vectors described above that specifically bind to pseudomonas Psl. In some embodiments, a method of making an isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl is provided, comprising: a) Culturing any of the host cells described above under conditions effective to express an antibody or antigen-binding fragment that specifically binds to pseudomonas Psl; and b) obtaining in the host cell an expressed antibody or antigen-binding fragment that specifically binds to Pseudomonas Psl.
In some embodiments, there is provided a method of treating a disease or disorder in an individual in need thereof, comprising administering to the individual an effective amount of an antibody or antigen-binding fragment that specifically binds pseudomonas Psl as described above, or a pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds pseudomonas Psl as described above. In some embodiments, there is provided the use of any one of the antibodies or antigen-binding fragments that specifically bind to pseudomonas Psl as described above, or a pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds to pseudomonas Psl as described above, in the manufacture of a medicament for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a pathogenic bacterial infection. In some embodiments, the infection is a gram negative bacterial infection. In some embodiments, the pathogen is pseudomonas aeruginosa. In some embodiments, the disease or condition comprises one or more symptoms caused by a pseudomonas aeruginosa infection. In some embodiments, the symptoms include one or more of fever, chills, fatigue, muscle and joint pain, joint swelling, headache, diarrhea, rash, wound pus, bacteremia, acute pneumonia, or intraperitoneal infection.
In some embodiments, any of the methods of treatment described above, wherein the method further comprises administering one or more therapeutic agents. In some embodiments, the at least one therapeutic agent is an antibiotic. In some embodiments, the antibiotic is one or more of imipenem, tobramycin, ciprofloxacin, meropenem, or a Qu Nazhong.
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising any one of the antibodies or antigen-binding fragments, nucleic acids, vectors, isolated host cells described above that specifically bind to pseudomonas Psl.
Drawings
The results shown in FIGS. 1A-1B are that the anti-Psl antibodies inhibited the adsorption of P.aeruginosa to A549 cells, as compared to control antibodies Wapr-001 or Cam-003. The results shown in FIGS. 1C-1D are the ability of anti-Psl antibodies to promote OPK against P.aeruginosa, as compared to control antibodies Wapr-001 or Cam-003.
The results shown in FIGS. 2A-2D are the ability of anti-Psl antibodies P59, 7H9, 3F12, 2A2 and 6G7 to block adsorption of P.aeruginosa strains O1-52/66 (FIG. 2A), O6-57/66 (FIG. 2B), O16-177/81 (FIG. 2C) or O2-53/66 (FIG. 2D) to A549 cells.
The results shown in FIGS. 3A-3D are the ability of anti-Psl antibodies P59, 7H9 and 3F12 to promote OPK against different strains O6-57/66 (FIG. 3A), O16-177/81 (FIG. 3B), O1-52/66 (FIG. 3C) or O2-53/66 (FIG. 3D), in comparison to the control antibody Psl 0096.
The results shown in FIGS. 4A-4D are the ability of anti-Psl antibody mutants P59-m21 or 7H9-m23 to block adsorption of P.aeruginosa strains O1-52/66 (FIG. 4A), O2-53/66 (FIG. 4B), O6-57/66 (FIG. 4C) or O16-177/81 (FIG. 4D) to A549 cells.
The results shown in FIGS. 5A-5D are the ability of the anti-Psl antibody mutant P59-m21 or 7H9-m23 to promote OPK against different strains O1-52/66 (FIG. 5A), O16-177/81 (FIG. 5B), O6-57/66 (FIG. 5C) or O2-53/66 (FIG. 5D) in comparison to the control antibody Psl 0096.
The ELISA results shown in FIGS. 6A-6B are binding specificities of anti-Psl antibodies 3F12, 7H9-m23 and P59-m21 to WFPA800 (FIG. 6A) strain or WFPA801 (FIG. 6B) strain.
The results shown in FIG. 7 are the cross-reactivity of anti-Psl antibodies 3F12, 7H9-m23 and P59-m21 with BV particles, in comparison with the control antibody, psl 0096.
The results shown in FIG. 8 are the ability of different doses of anti-Psl antibody 3F12, 7H9-m23 or P59-m21 to inhibit P.aeruginosa biofilm formation, in comparison to the control antibody Psl 0096.
FIG. 9A shows the ability of anti-Psl antibody P59 to increase survival at a dose of 15mg/kg based on the weight of mice in a mouse bacteremia model with a 2-fold lethal dose (2 XLD 90) inoculated with P.aeruginosa (57/66), compared to control antibody Cam-003.
FIG. 9B shows the ability of anti-Psl antibodies P59, 1D10, 7H9, 2A2 or 6G7 to increase survival at a dose of 10mg/kg based on mouse body weight in a mouse bacteremia model with a 3-fold lethal dose (3 XLD 90) of Pseudomonas aeruginosa (57/66) as compared to control antibody Cam-003.
FIG. 9C shows the ability of anti-Psl antibody 3F12 or 7H9 to increase survival at a dose of 10mg/kg based on mouse body weight in a mouse bacteremia model with a 4-fold lethal dose (4 XLD 90) inoculated with P.aeruginosa (57/66), as compared to control antibody Psl 0096.
FIG. 9D shows the ability of anti-Psl antibody mutants 7H9-m23, 7H9-m24, 7H9-m25, 3F12-m01 or P59-m21 to increase survival in a mouse bacteremia model with a 4-fold lethal dose (4 XLD 90) of P.aeruginosa (57/66) at a dose of 10mg/kg given to the body weight of the mice.
The results shown in FIG. 10 are the ability of anti-Psl antibody mutants 3F12-m01, 7H9-m24 or P59-m21 to reduce organ bacterial load in lung, spleen, kidney.
The results shown in FIG. 11 are the ability of anti-Psl antibody 3F12 to increase survival in mice when administered alone or in combination with the antibiotics meropenem (MEM), tobramycin (TOB) or Ciprofloxacin (CIP) in a model of intraperitoneal infection with a 3-fold lethal dose (3 XLD 90) of Pseudomonas aeruginosa (57/66) inoculum.
FIG. 12 shows the pharmacokinetics of anti-Psl antibodies 3F12, 7H9-m23, P59-m21 and control antibody Psl0096 in rats at an intravenous dose of 3 mg/kg.
Detailed description of the application
In one aspect, the application provides antibodies or antigen-binding fragments that specifically bind to pseudomonas Psl. Through a combination of scFv phage library screening, affinity maturation, and appropriately designed biochemical and biological experiments, we have identified highly potent antibody molecules capable of specifically binding Psl that inhibit pseudomonas aeruginosa adsorption to a549 cells and promote OPK to pseudomonas aeruginosa, as well as provide therapeutic and prophylactic protection against pseudomonas aeruginosa in vivo.
Antibodies or antigen-binding fragments provided herein that specifically bind to pseudomonas Psl include, for example, full length anti-Psl antibodies, anti-Psl single chain antibodies (scFvs), anti-Psl Fc fusion proteins, multi-specific (e.g., bispecific) anti-Psl antibodies, anti-Psl immunoconjugates, and the like.
In some embodiments, antibodies or antigen-binding fragments that specifically bind to pseudomonas Psl having a specific sequence are also provided, as well as antibodies that compete with these antibodies or antigen-binding fragments or bind to the same epitope.
Also provided are nucleic acids encoding antibodies or antigen-binding fragments that specifically bind to pseudomonas Psl, compositions comprising anti-Psl antibodies, and methods of making and using anti-Psl antibodies.
Definition of the definition
As used herein, a "treatment" or "treatment" is a method of achieving a beneficial or desired result, including clinical results. In view of the objects of the present application, such beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, alleviating the extent of the disease, stabilizing the disease (e.g., preventing or delaying exacerbation of the disease), preventing or delaying the spread of the disease (e.g., systemic spread of pathogenic bacteria), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, alleviating the disease (partially or wholly), reducing the dosage of one or more other drugs required to treat the disease, delaying the progression of the disease, improving or enhancing quality of life, increasing weight, and/or prolonging survival. Meanwhile, "treatment" also includes reduction of the pathological outcome of the infection (e.g., host cell lysis or necrosis). The methods of the present application contemplate any one or more aspects of these treatments.
The term "prevent" and similar words, such as "prevent", "preventing" and "prevention", etc., mean a method of preventing, inhibiting or reducing the likelihood of occurrence or recurrence of a disease or disorder, such as a pathogen infection. It also refers to delaying the onset or recurrence of a disease or disorder, or delaying the onset or recurrence of symptoms of a disease or disorder. As used herein, the term "prevent" and similar terms also include alleviating the intensity, impact, symptoms and/or burden of a disease or disorder before it occurs or recurs. As used herein, the term "prevent" and similar terms also include reducing the risk of occurrence or recurrence of a disease or disorder, and susceptibility to infection by a pathogen, for example.
The term "antibody" includes full length antibodies and antigen binding fragments thereof. Full length antibodies include two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable region in both chains typically comprises 3 hypervariable loops, known as Complementarity Determining Regions (CDRs) (light chain (LC) CDRs comprise LC-CDR1, LC-CDR2 and LC-CDR3, and Heavy Chain (HC) CDRs comprise HC-CDR1, HC-CDR2 and HC-CDR 3). CDR boundaries of antibodies or antigen binding fragments disclosed herein may be defined or identified by Kabat, chothia or Al-Lazikani conventions (Al-Lazikani 1997;Chothia 1985;Chothia 1987;Chothia 1989;Kabat 1987;Kabat 1991). The 3 CDR regions of the heavy or light chain are inserted between flanking segments called Framework Regions (FRs) which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit multiple effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five main classes or isotypes of antibodies are IgA, igD, igE, igG and IgM, which are characterized by having heavy chains of the alpha, delta, epsilon, gamma and mu types, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (gamma 1 heavy chain), igG2 (gamma 2 heavy chain), igG3 (gamma 3 heavy chain), igG4 (gamma 4 heavy chain), igA1 (alpha 1 heavy chain n) or IgA2 (alpha 2 heavy chain).
As used herein, the term "antigen-binding fragment" includes an antibody fragment, including, for example, diabody (diabody), fab ', F (ab') 2, fv fragment, disulfide stabilized Fv fragment (dsFv), (dsFv) 2 Bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabodies (ds diabodies), single chain antibodies (scFv), scFv dimers (diabodies), multispecific antibodies consisting of antibody fragments comprising one or more CDRs, single domain antibodies, nanobodies, domain antibodies, diabody antibodies, or any other antibody fragment capable of binding an antigen but not comprising an intact antibody structure. Antigen binding fragments also include fusion proteins comprising the above antibody fragments. The antigen binding fragment is capable of binding the same antigen as the parent antibody or parent antibody fragment (e.g., parent scFv). In some embodiments, an antigen binding fragment may include one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. Two antibodies or antibody portions may bind to the same epitope on an antigen if they exhibit competitive binding to that antigen.
As described herein, a first antibody "competes" with a second antibody for binding to a Psl target when the first antibody inhibits the second antibody from binding to the Psl target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at equimolar concentrations, and vice versa. PCT publication WO 03/48731 describes a high throughput antibody "epitope categorization" method based on cross-competition.
As used herein, the term "specifically binds," "specifically recognizes," or "specific for," refers to a measurable and reproducible interaction, e.g., binding of an antibody to a target can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody being able to specifically recognize a target (which may be an epitope) means that the antibody binds to the target with a higher affinity, avidity, easier and/or longer lasting than other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity that is at least 10-fold greater than its binding affinity to other targets.
As used herein, an "isolated" anti-Psl antibody refers to an anti-Psl antibody that (1) is independent of naturally occurring proteins, (2) does not contain other proteins of the same origin, (3) is expressed by cells of different species, or (4) is not found in nature.
As used herein, the term "isolated nucleic acid" refers to nucleic acids of genomic, cDNA, or synthetic origin, or a combination thereof. Depending on its source, the "isolated nucleic acid" (1) is not related to all or part of the polynucleotides found in nature in "isolated nucleic acids" (2) may be operably linked to polynucleotides that are not naturally associated therewith, or (3) may not be present in nature as part of a longer sequence.
As used herein, the term "CDR" or "complementarity determining region" refers to a discontinuous antigen binding site found within the variable domains of heavy and light chain polypeptides. J.biol.chem.252:6609-6616 (1977); kabat et al, U.S. Dept. Of Health and Human Services, "Sequences of proteins of immunological interest" (1991); chothia et al, J.mol.biol.196:901-917 (1987); al-Lazikani B.et Al, J.mol.biol.,273:927-948 (1997); macCallum et al, J.mol. Biol.262:732-745 (1996); abhinandan and Martin, mol. Immunol.,45:3832-3839 (2008); lefranc M.P.et al, dev.Comp.Immunol.,27:55-77 (2003); and honeygger and Pluckthun, J.mol.biol.,309:657-670 (2001), wherein these definitions include the coincidence or subset of amino acid residues when compared to each other. However, any definition of a CDR for an antibody or grafted antibody or variant thereof is intended to be included within the terms defined and used herein. The positions of the amino acid residues comprised by the CDRs defined by the various references cited above are listed in table 1 to illustrate the comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, abhinandan and Martin, mol.immunol.,45:3832-3839 (2008); ehrenmann F.et al, nucleic Acids Res.,38:D301-D307 (2010); and Adolf-Bryfogle J.et al, nucleic Acids Res.,43:D432-D438 (2015). The content of the references cited in this paragraph is hereby incorporated by reference in its entirety for the purposes of the present application and possibly in one or more of the claims contained herein.
TABLE 1 CDR definition
Kabat 1 Chothia 2 MacCallum 3 IMGT 4 AHo 5
V H CDR1 31-35 26-32 30-35 27-38 25-40
V H CDR2 50-65 53-55 47-58 56-65 58-77
V H CDR3 95-102 96-101 93-101 105-117 109-137
V L CDR1 24-34 26-32 30-36 27-38 25-40
V L CDR2 50-56 50-52 46-55 56-65 58-77
V L CDR3 89-97 91-96 89-96 105-117 109-137
1 Amino acid residue numbering refers to the nomenclature used in Kabat et al, supra
2 Amino acid residue numbering refers to the nomenclature used in Chothia et al, supra
3 Amino acid residue numbering refers to the nomenclature used in MacCallum et al, supra
4 Amino acid residue numbering refers to the nomenclature used in the above-mentioned Lefranc et al
5 Amino acid residue numbering refers to the naming method in Honygger and Pluckthun, supra
The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they possess the biological activity of the application (see U.S. patent No.4,816,567; and Morrison et al, proc.Natl. Acad. Sci. USA,81:6851-6855 (1984)).
"Fv" is the smallest antibody fragment that contains the complete antigen recognition and binding site. The fragment is a dimer formed by the tight non-covalent linkage of one heavy chain variable domain and one light chain variable domain. By folding of these two domains, 6 hypervariable loops (3 loops in each of the light and heavy chains) were derived, which Gao Bianhuan provided the amino acid residues for the antibody to bind antigen and confer specificity to the antibody for binding to antigen. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, although with less affinity than the complete binding site.
"Single chain Fv",may also be abbreviated as "sFv" or "scFv", are compositions comprising V linked as a single polypeptide chain H And V L Antibody fragments of the antibody domains. In some embodiments, the scFv polypeptide further comprises V H And V L A linker polypeptide between the domains, which allows the scFv to form the desired structure for antigen binding. For a summary of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, rosenburg and Moore eds., springer-Verlag, new York, pp.269-315 (1994).
The term "diabodies" refers to antibodies that bind to a polypeptide at V H And V L A small antibody fragment is prepared by constructing scFv fragments (see above) with short linkers (e.g., 5-10 residues) between the domains, which allows the variable domains to pair between the chains rather than within the chains, resulting in a bivalent fragment, i.e., a fragment with two antigen binding sites. Bispecific diabodies are heterodimers of two "cross" scFv fragments, wherein V of both antibodies H And V L Domains are located on different polypeptide chains. In EP 404,097; WO 93/11161; diabodies are described fully in Hollinger et al, proc.Natl.Acad.Sci.USA,90:6444-6448 (1993).
The "humanized" form of a non-human (e.g., rodent) antibody is a chimeric antibody that includes minimal sequences from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient antibody are replaced by residues from a hypervariable region of a non-human species, such as mouse, rat, rabbit or non-human primate, having the desired antibody specificity, affinity and performance (donor antibody). In some cases, residues in the Framework Region (FR) of the human immunoglobulin are replaced with corresponding non-human residues. In addition, humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For specific details, reference may be made to Jones et al, nature 321:522-525 (1986); riechmann et al, nature 332:323-329 (1988); and Presta, curr.Op.struct.biol.2:593-596 (1992).
The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as: sequence comparison is performed where conservative substitutions are considered to be part of the sequence identity, the percentage of amino acid residues in the candidate sequence that are identical to the polypeptide sequence to be compared. The percentage of amino acid sequence identity may be determined by a variety of alignment methods within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine suitable parameters for measuring the alignment, including any algorithms needed to achieve maximum alignment over the full length of the compared sequences. However, for purposes herein, the percent amino acid sequence identity values were generated using the sequence alignment computer program MUSCLE (Edgar, R.C., nucleic Acids Research (5): 1792-1797,2004; edgar, R.C., BMC Bioinformatics (1): 113,2004).
The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR of the application is one that binds an IgG antibody (a gamma receptor), including receptors of the fcyri, fcyrii, and fcyriii subclasses, including allelic variants and alternatively spliced forms of these receptors. Fcyrii receptors include fcyriia (activating receptor) and fcyriib (inhibiting receptor), which have similar amino acid sequences, differing primarily in the cytoplasmic domain. The cytoplasmic domain of the activating receptor fcyriia contains an immune receptor tyrosine activation motif (ITAM). The cytoplasmic domain of the inhibition receptor fcyriib contains the Immunoreceptor Tyrosine Inhibitory Motif (ITIM) (see m.in Annu.Rev.Immunol.15:203-234 (1997)). The term also includesThe allotypes, for example, fcgammaRIIIA allotype, fcgammaRIIIA-Phe 158, fcgammaRIIIA-Val 158, fcgammaRIIA-R131 and/or FcgammaRIIA-H131. At Ravetch and Kinet, annu.Rev.Immunol 9:457-92 (1991) and Capel et al, immunomets 4:25-34 (1994); and de Haas et al, J.Lab.Clin.Med.126:330-41 (1995) describes FcRs. The term FcR in the present application encompasses other types of FcRs, including FcRs identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for transferring the parent IgGs to neonates (Guyer et al, j.immunol.
117:587(1976)and Kim et al.,J.Immunol.24:249(1994))。
The term "FcRn" refers to neonatal Fc receptor (FcRn). FcRn is structurally similar to the Major Histocompatibility Complex (MHC), consisting of non-covalent binding of the alpha chain to beta 2 microglobulin. The various functions of the neonatal Fc receptor FcRn are described in Ghetie and Ward (2000) Annu. Rev. Immunol.18,739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from the mother to neonates and in the regulation of serum IgG levels. FcRn acts as a salvage receptor that can bind and transport endocytosed IgG in intact form within and between cells and protect them from the default degradation pathway.
The "CH1 domain" of the human IgG Fc region generally extends from amino acid 118 to amino acid 215 (EU numbering system).
The "hinge region" is generally defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, molecular immunol.22:161-206 (1985)). The hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine residues that form the inter-heavy chain disulfide bond in the same position as IgG 1.
The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. The CH2 domain is unique in that it does not mate tightly with another region, but rather inserts two N-terminally linked branched carbohydrate chains between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable. Burton, molecular immunol.22:161-206 (1985).
The "CH3" domain includes the extension from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminal end of the antibody sequence, typically amino acid 446 or 447 of IgG) within the Fc region.
The "functional Fc fragment" has the "effector function" possessed by the native Fc region sequence. Exemplary "effector functions" include C1q binding; complement Dependent Cytotoxicity (CDC); fc receptor binding; antibody dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector functions typically require that the Fc region bind to a binding domain (e.g., an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
Antibodies to IgG Fc variants having "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the parent polypeptide or polypeptide comprising the native Fc sequence. Fc variants exhibiting "enhanced binding" to FcR have a higher binding affinity (e.g., lower apparent Kd or IC50 value) to at least one FcR than the parent polypeptide or polypeptide comprising the native IgG Fc sequence. In some embodiments, the binding capacity is increased by a factor of 3, e.g., 5, 10, 25, 50, 60, 100, 150, 200, even up to a factor of 500 or the binding capacity is increased by a factor of 25% to 1000% as compared to the parent polypeptide. Fc variants exhibiting "reduced binding" to FcR have lower affinity (e.g., higher apparent Kd or IC50 values) for at least one FcR than the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
"antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity, meaning that secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells, such as natural killer cells (NK), neutrophils and macrophages, enabling these cytotoxic effector cells to specifically bind antigen-bearing target cells, followed by killing of the target cells with cytotoxins. Antibodies "arm" cytotoxic cells and are necessary for such killing. In the major cell types mediating ADCC NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. FcR expression on hematopoietic cells is summarized in Table 3 at page 464 of Ravetch and Kinet, annu.Rev.Immunol 9:457-92 (1991). The ADCC activity of the target molecule is assessed and an in vitro ADCC assay may be performed and is described in U.S. patent nos. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include Peripheral Blood Mononuclear Cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule may also be assessed in vivo, for example as in Clynes et al PNAS (USA)
95:652-656 (1998).
Polypeptides comprising an Fc region variant that are experimentally substantially the same in number as wild-type IgG Fc polypeptides (or parent polypeptides) are more effective in mediating ADCC in vitro or in vivo when they exhibit "enhanced ADCC activity" or are capable of mediating ADCC effects more effectively in the presence of human effector cells than wild-type IgG Fc polypeptides or parent polypeptides. Such variants are typically identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, e.g., in animal models, etc. In some embodiments, such variants mediate ADCC with a 5 to 100 fold, e.g., 25 to 50 fold increase in efficiency compared to the wild-type Fc (or parent polypeptide).
"complement dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by binding of the first component of the complement system (C1 q) to antibodies (subclasses of appropriate structure) that bind to cognate antigens. To assess complement activation, CDC experiments may be performed as described in Gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996). Polypeptide variants having altered amino acid sequences of the Fc region and increased or decreased C1q binding capacity are described in U.S. Pat. No.6,194,551B1 and WO 99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al J.Immunol.164:4178-4184 (2000).
Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence. The nucleotide sequence encoding a protein or RNA may also include introns, e.g., the nucleotide sequence encoding a protein may in some forms comprise introns.
The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence such that the latter is expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Typically, operably linked DNA sequences are contiguous and, if necessary, two protein coding regions can be linked in the same reading frame.
"homology" refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences is the same base or amino acid monomer subunit, for example, the same position of both DNA molecules is adenine, then both DNA molecules are homologous at that position. The percentage of homology between two sequences refers to the function of the ratio of the number of matching or homologous positions to the total number of positions shared by the two sequences multiplied by 100. For example, if 6 of the 10 positions in two sequences are matched or homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. In general, when two sequences are aligned, alignment is performed with the aim of obtaining maximum homology.
An "effective amount" of an anti-Psl antibody or composition as disclosed herein refers to an amount sufficient to achieve a particular purpose. The "effective amount" may be determined empirically and by methods known in connection with the purpose.
The term "therapeutically effective amount" refers to an amount of an anti-Psl antibody or composition described herein that is effective to "treat" a disease or disorder in an individual. In the case of a pseudomonas aeruginosa infection, a therapeutically effective amount of the anti-Psl antibodies or compositions disclosed herein can reduce the number of infected cells, inhibit (i.e., slow and preferably stop to some extent) the spread of the infection, and/or alleviate to some extent one or more symptoms associated with the infection. Upon infection, the anti-Psl antibodies or compositions disclosed herein are capable of inhibiting the growth of and/or killing pseudomonas aeruginosa, which may be cytostatic and/or cytotoxic. In some embodiments, a therapeutically effective amount refers to an amount that inhibits infection in a patient. In some embodiments, a therapeutically effective amount refers to an amount that completely clears an infection in a patient.
As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to materials that are not biologically active or otherwise undesirable, e.g., that can be added to a pharmaceutical composition administered to a patient without causing significant adverse biological reactions or interacting in a deleterious manner with any of the other components of the composition in which they are contained. The pharmaceutically acceptable carrier or excipient preferably meets the desired criteria for toxicology or manufacturing testing and/or is contained in inactive ingredient guidelines established by the U.S. food and drug administration.
The embodiments of the application described herein should be understood to include embodiments consisting of … … and/or consisting essentially of … ….
Reference herein to "about" is a numerical value or parameter, including (and describing) variations on the value or parameter itself. For example, a description relating to "about X" includes a description of "X".
As used herein, reference to a value or parameter that is "not (not)" generally means and describes "other than (other than)" a value or parameter. For example, the method cannot be used to treat type X infections, meaning that the method is generally used to treat other types of infections besides type X.
As used herein and in the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
anti-Psl antibodies
In one aspect, the applicationanti-Psl antibodies are provided that specifically bind to Psl. Such anti-Psl antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibody human antibodies, and antibody molecules comprising heavy and/or light chain CDRs as described herein. In one aspect, the application provides isolated antibodies that bind to Psl. Contemplated anti-Psl antibodies include, for example, full length anti-Psl antibodies (e.g., full length IgG1, igG2, or IgG 4), anti-Psl single chain antibodies, multispecific (e.g., bispecific) anti-Psl antibodies, anti-Psl immunoconjugates, and the like. In some embodiments, the anti-Psl antibody is a Fab, fab ', F (ab) '2, fab ' -SH, single chain antibody (scFv), fv fragment, dAb, fd, nanobody, diabody, or linear antibody. In some embodiments, an antibody that specifically binds to Psl means that the antibody binds to Psl with at least 10 times greater affinity than the binding affinity to a non-target (including, e.g., 10 2 、10 3 、10 4 、10 5 、10 6 Or 10 7 Multiple). In some embodiments, non-target refers to an antigen that is not Psl. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence Activated Cell Sorting (FACS) analysis, or Radioimmunoassay (RIA). Kd values can be determined by methods known in the art, such as Surface Plasmon Resonance (SPR) techniques or Biological Layer Interference (BLI) techniques.
In some embodiments, the anti-Psl antibody or antigen binding fragment that specifically binds to pseudomonas Psl (a) promotes, mediates, or enhances opsonophagocytic killing (OPK) of pseudomonas aeruginosa, and/or (b) inhibits adsorption of pseudomonas aeruginosa to epithelial cells.
While anti-Psl antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed broadly herein, non-human anti-Psl antibodies are also contemplated. In some embodiments, the non-human anti-Psl antibodies include human CDR sequences and non-human framework region sequences of the anti-Psl antibodies described herein, and in some embodiments, the non-human framework region sequences include any sequences for producing heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, such as mice, rats, rabbits, pigs, cattle (e.g., cattle, bulls, buffalo), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., marmosets, macaques), and the like. In some embodiments, the non-human anti-Psl antibodies comprise anti-Psl antibodies produced by grafting one or more of the human CDR sequences described herein into a non-human framework region (e.g., a murine or chicken framework region sequence).
In some embodiments, the anti-Psl antibodies described herein specifically recognize an epitope in pseudomonas Psl. In some embodiments, the anti-Psl antibody is pseudomonas Psl specific and does not cross react with other types of proteins.
In some embodiments, the anti-Psl antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG1 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG2 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG3 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG4 type heavy chain constant region. In some embodiments, the IgG refers to human IgG. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 160. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 161. In some embodiments, the anti-Psl antibody comprises a lambda light chain constant region. In some embodiments, the anti-Psl antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 162. In some embodiments, the anti-Psl antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
In one aspect, the application provides an isolated anti-Psl antibody, wherein the anti-Psl antibody comprises a heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, or variants comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; an HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23 or a variant comprising up to 3 (e.g.1, 2 or 3) amino acid substitutionsA body; an HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34 or variants comprising up to 3 (e.g.1, 2 or 3) amino acid substitutions.
In some embodiments, the anti-Psl antibody comprises a light chain variable region (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising any one of the amino acid sequences of SEQ ID NOs 38-39, 41-49, or variants comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 52-53, 55-61, or a variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions; an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75 or variants comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, or variants comprising up to 3 (e.g., 1, 2 or 3) amino acid substitutions; a HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23 or variants comprising up to 3 (e.g.1, 2 or 3) amino acid substitutions; a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34 or variants comprising up to 3 (e.g.1, 2 or 3) amino acid substitutions; one (V) L ) The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs 38-39, 41-49, or a variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions; an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs 52-53, 55-61, or a variant comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions; an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75 or variants comprising up to 3 (e.g. 1, 2 or 3) amino acid substitutions.
In some embodiments, the amino acid substitutions described above are limited to only the "exemplary substitutions" shown in table 8 of the present application. In some embodiments, amino acid substitutions are limited to the "preferred substitutions" shown in table 8 of the present application.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, a HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23, and a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 38-39, 41-49, an LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 52-53, 55-61, and an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising a V having the amino acid sequence of any one of SEQ ID NOs 80-81, 83-90, 159 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence of any one of SEQ ID NOs 92-93, 95-97, 99-104 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (ii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (iv) V (V) H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, one comprising the amino acid sequenceHC-CDR2 of SEQ ID NO. 18 and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (v) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (vi) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (vii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (viii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (ix) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; (x) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; or (xi) V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 34HC-CDR3; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants.
In some embodiments, the anti-Psl antibody comprises: (i) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 64, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iv) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (v) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vi) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR2 comprising the amino acid sequence SELC-CDR3 of Q ID NO 71 or V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (viii) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ix) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (x) V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (xi) V L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises: (i) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ii) V (V) H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and one HC-CDR2 comprisingHC-CDR3 of amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 64, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (iv) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (v) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68 or at most in the LC-CDRs V with 5 amino acid substitutions L Variants; (vi) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (vii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (viii) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (ix) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The sum ofThe V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; (x) V (V) H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants; or (xi) V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90, 159 or comprising variant sequences having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90, 159, and V L The V is L Comprises any of the amino acid sequences of SEQ ID NOs 92-93, 95-97, 99-104, or comprises at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99) of the amino acid sequences of any of the SEQ ID NOs 92-93, 95-97, 99-104% of sequence homology. In some embodiments, the anti-Psl antibody comprises a V comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90, 159 H And V comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97, 99-104 L 。
In some embodiments, the anti-Psl antibody is a full length antibody. In some embodiments, the anti-Psl antibody comprises an IgG1 constant region. In some embodiments, the IgG1 refers to human IgG1. In some embodiments, the anti-Psl antibody comprises an IgG4 constant region. In some embodiments, the IgG4 refers to human IgG4. In some embodiments, the anti-Psl antibody heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 160. In some embodiments, the anti-Psl antibody heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 161. In some embodiments, the anti-Psl antibody light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 162.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 80 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 92 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 81 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 93 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 83 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 95 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 84 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 96 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-cancer agentPsl antibodies include V H The V is H Comprising V having SEQ ID NO 85 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 97 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 86 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 99 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 81 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 100 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 87 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 101 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 88 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 102 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 89 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 103 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 90 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 104 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 159 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 95 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, one HC-CDR1 comprising the amino acid sequence SEQHC-CDR2 of ID No. 14, and HC-CDR3 comprising the amino acid sequence of SEQ ID No. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 80, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 80, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 92, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 92. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 80 H V comprising the amino acid sequence SEQ ID NO. 92 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 80 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:92 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and one HC-CDR2 comprising ammoniaHC-CDR3 of the base acid sequence SEQ ID NO. 26, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID No. 39, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 53, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 64, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 64. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 64. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 64.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 81, or a variant sequence comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to the amino acid sequence SEQ ID NO. 81, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 93, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 93. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 81 H V comprising the amino acid sequence SEQ ID NO:93 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 81 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:93 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibodyThe antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 83, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 83, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 95, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 95. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 83 H V comprising the amino acid sequence SEQ ID NO 95 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 83 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs 95 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO 159, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO 159, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 95, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 95. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 159 H V comprising the amino acid sequence SEQ ID NO 95 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO 159 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs 95 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67. In some embodiments, a method is providedanti-Psl antibodies that specifically compete with antibodies comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 84, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 84, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 96, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 96. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 84 H V comprising the amino acid sequence SEQ ID NO:96 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO 84 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:96 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments of the present invention, in some embodiments,the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an amino acid sequence comprisingLC-CDR3 of the amino acid sequence SEQ ID NO. 68.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 85, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 85, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 97, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 97. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:85 H V comprising the amino acid sequence SEQ ID NO 97 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 85 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs 97 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO 44, a packageLC-CDR2 comprising the amino acid sequence SEQ ID No. 57, and LC-CDR3 comprising the amino acid sequence SEQ ID No. 70. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 86, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 86, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 99, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 99. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 86 H V comprising the amino acid sequence SEQ ID NO 99 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 86 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising a catalyst having ammoniaV of the base acid sequence SEQ ID NOs 99 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 81, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 81, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 100, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 100. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 81 H V comprising the amino acid sequence SEQ ID NO. 100 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 81 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:100 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and one comprising an amino acidHC-CDR3 of SEQ ID NO. 31; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 87, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 87, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 101, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 101. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 87 H V comprising the amino acid sequence SEQ ID NO. 101 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 87 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs 101 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, a LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and a LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: one comprising the amino acid sequence SEQ ID NO. 10HC-CDR1, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21 and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 88, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 88, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 102, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 102. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 88 H V comprising the amino acid sequence SEQ ID NO. 102 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 88 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:102 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID No. 48, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 60, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 74, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The sum ofThe V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 89, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 89, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 103, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 103. In some embodiments, the anti-Psl antibody comprises a polypeptide comprisingV of amino acid sequence SEQ ID NO. 89 H V comprising the amino acid sequence SEQ ID NO. 103 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 89 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs:103 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34, or variants comprising up to 5 amino acid substitutions in the HC-CDRs; v (V) L The V is L Comprising: a LC-CDR1 comprising the amino acid sequence SEQ ID No. 49, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 61, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 75, or variants comprising up to 5 amino acid substitutions in the LC-CDRs.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75. In some embodiments, a method is providedAn anti-Psl antibody that binds to the same epitope as an antibody comprising V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75.
In some embodiments, the Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 90, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 90, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 104, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 104. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 90 H V comprising the amino acid sequence SEQ ID NO 104 L . In some embodiments, the anti-Psl antibody comprises V H Comprising V having the amino acid sequence SEQ ID NO. 90 H HC-CDR1, HC-CDR2 and HC-CDR3 in (a); v (V) L Comprising V having the amino acid sequence SEQ ID NOs 104 L LC-CDR1, LC-CDR2 and LC-CDR3 in (a).
In one aspect, the application provides an isolated anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising IHSVH (SEQ ID NO: 4), or a variant thereof comprising up to 3 amino acid substitutions; one HC-CDR2 comprising TIISSGTTTTYAQSFQD (SEQ ID NO: 16), or a variant thereof comprising up to 3 amino acid substitutions; and an HC-CDR3 comprising X 1 X 2 X 3 X 4 (SEQ ID NO: 189), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 D, Y or N, X 2 Is G or A，X 3 Is D or T, X 4 S, A or T; v (V) L The V is L Comprising the following steps: one LC-CDR1 comprising RASQGISSWLA (SEQ ID NO: 40), or a variant thereof comprising up to 3 amino acid substitutions; an LC-CDR2 comprising HASTLES (SEQ ID NO: 54), or a variant thereof comprising up to 3 amino acid substitutions; and an LC-CDR3 comprising LQAX 1 SLPTH (SEQ ID NO: 158), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, D, Y, F, P, G, K, H, A, C, E, Q, R, S, T, V, W or L.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 105 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 106 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 107 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO. 108 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 109 H HC-CDR1, HC-CDR2 and HC-CD of (2)R3 and V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 110 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 111 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 112 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 113 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 114 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 115 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 116 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-cancer agentPsl antibodies include V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 117 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 118 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 119 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 120 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 121 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 122 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 123 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The saidV L Comprising V having SEQ ID NO 124 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 125 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 126 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 82 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 127 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 107 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO 113 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 107 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 123 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a). In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising V having SEQ ID NO 107 H HC-CDR1, HC-CDR2 and HC-CDR3 of (C), V L The V is L Comprising V having SEQ ID NO. 116 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or comprising up to 5 amino acid residues in the HC-CDRs V of the generation H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising at least 90% of the amino acid sequence SEQ ID NO. 82Variant sequences of (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 165, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 165; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-P is provided that specifically competes with an antibody sl antibodies, which include V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 165; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 165; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 105, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 105, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 105 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 105 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodimentsIn one example, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 166, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 166; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 166; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 166; v (V) L The V is L Comprising: one comprising the amino acid sequence SEQ ID NO. 40 and one comprising the amino acid sequence SEQLC-CDR2 of ID No. 54, and an LC-CDR3 comprising the amino acid sequence of SEQ ID No. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 106, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 106, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 106 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 106 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35;v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The sum ofThe V is H Comprising V having the amino acid sequence SEQ ID NO. 107 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 167, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 167; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 167; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: one or more of HC-CDR1 comprising amino acid sequence SEQ ID NO. 4, HC-CDR2 comprising amino acid sequence SEQ ID NO. 16, and HC-CDR3 comprising amino acid sequence SEQ ID NO. 167; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 108, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 108, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 108 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 108 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 168, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 168; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 168; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 168; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 109, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 109, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%) of the amino acid sequence SEQ ID NO. 9497%, 98% or 99%) sequence homology. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 109 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 109 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 199, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 199. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: comprising an amino acid sequenceLC-CDR1 of SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 199. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 199.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 111, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 111. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO 111 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:111 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H VariantsThe method comprises the steps of carrying out a first treatment on the surface of the V (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 200, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 200. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 200. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 200.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a sequence which is at least 90% (e.g. at least 91%),92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 112, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 112. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO 112 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 112 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody thatComprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 113, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 113. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:113 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:113 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibodyThe body comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 201, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 201. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 201. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, andan LC-CDR3 comprising the amino acid sequence SEQ ID NO. 201.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 114, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 114. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 114 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:114 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 202, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 202. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 202. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 202.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 115, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 115. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 115 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 115 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: comprising an amino acid sequenceHC-CDR1 of SEQ ID NO. 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16 and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 116, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 116. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:116 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:116 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 203, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 203. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 203. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 203.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 117 or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or more) of the amino acid sequence SEQ ID NO. 11799%) sequence homology. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 117 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:117 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 204, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 204. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-C comprising the amino acid sequence SEQ ID NO. 40DR1, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 204. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 204.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 118, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 118. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:118 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:118 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 205, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 205. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 205. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 205.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising at least 90% (e.g. at least 91%, 92%, 93% >, a sequence which is identical to the amino acid sequence SEQ ID NO. 82,94%, 95%, 96%, 97%, 98% or 99%) sequence homology, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 119, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 119. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:119 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:119 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 206, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 206. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 206. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 206.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 120, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 120. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 120 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 120 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprisesV H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 207, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 207. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 207. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and a packageLC-CDR3 comprising the amino acid sequence SEQ ID NO. 207.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 121, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 121. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 121 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 121 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 208, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 208. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 208. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 208.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 122, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 122. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 122 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprises a structure withV of amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:122 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: comprising the amino acid sequence SEQ ID NO 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 123, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 123. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 123 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:123 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 209, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 209. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 209. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 209.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 124, or comprising a sequence at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) from the amino acid sequence SEQ ID NO. 124Variant sequences of column homology. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO 124 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 124 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 210, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 210. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: one comprising the amino acid sequence of SEQ ID NO. 40, one LC-CDR1An LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 210. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 210.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 125, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 125. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO. 125 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:125 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The sum ofThe V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95% >, a sequence which is identical to the amino acid sequence SEQ ID NO. 82, 96%, 97%, 98% or 99%) sequence homology, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 126, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 126. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:126 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:126 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 212, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 212. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 212. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 27; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 212.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 82, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 127, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 127. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 82 H And V comprising the amino acid sequence SEQ ID NO:127 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 82 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:127 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 76. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR comprising the amino acid sequenceLC-CDR3 of SEQ ID NO 76.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 113, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 113. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO:113 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 107 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:113 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Included: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 77.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 123, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 123. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO. 123 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprises a polypeptide having the amino acid sequence SV of EQ ID NO:107 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:123 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: an HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4,a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16 and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 35; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 78.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 107, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 107, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 116, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 116. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO:116 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 107 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:116 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 169 or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In one placeIn some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 169; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 169; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 4, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 16, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 169; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 40, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 54, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 65.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 110, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 110, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 94, or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 94Is a variant of (a) a sequence of (c). In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 110 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 110 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:94 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In one aspect, the application provides an isolated anti-Psl antibody comprising V H The V is H Comprising the following steps: one HC-CDR1 comprising SSGDYWG (SEQ ID NO: 1), or a variant thereof comprising up to 3 amino acid substitutions; comprising SIHNX 1 GSTYYNPSLKG (SEQ ID NO: 213), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 S, K or Q; and one containing QFGSETYYX 1 GIX 2 HC-CDR3 of P (SEQ ID NO: 190), or variants thereof comprising up to 3 amino acid substitutions, wherein X 1 N, S, V, T or P, X 2 D, Y, C, H, S, R, A, E, G, K, W, V or Q; v (V) L The V is L Comprising the following steps: comprising RSSQSLLHSX 1 LC-CDR1 of GYNYLD (SEQ ID NO: 184), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, A, V, F, R, G, H, Q, W or P; an LC-CDR2 comprising lgsnas (SEQ ID NO: 51), or a variant thereof comprising up to 3 amino acid substitutions; and one containing MQALQTPX 1 LC-CDR3 of T (SEQ ID NO: 214), wherein X 1 Is R or Y, or a variant thereof comprising up to 3 amino acid substitutions.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising: a polypeptide comprising the amino acid sequence SEQ ID NO:37, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 51, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 62, or V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 79, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 79And V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 79 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 79 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 170, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 170; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: HC (hybrid protein) comprising the amino acid sequence SEQ ID NO. 1CDR1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 170; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 170; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 128, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 128, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 128 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 128 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: comprising the amino acid sequence SEQ ID NHC-CDR1 of O.1, HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163 and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 171 or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 171; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 171; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 171; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 129, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 129, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:129 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 129 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 172, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 172; v (V) L The V is L Comprising: one comprising the amino acid sequence of SEQ ID NO. 37, one LC-CDR1An LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 172; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 172; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 130, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 130, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 130 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 130 H HC-CDR1, HC-CDR2 and HC-CDR3;v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 173, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 173; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 173; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO 173; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 131, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 131, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 131 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 131 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The saidV H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 132, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 132, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprisesV comprising the amino acid sequence SEQ ID NO. 132 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 132 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 174, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 174; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 174; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR2 comprising the amino acid sequenceLC-CDR3 of SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 174; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:133, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO:133, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:133 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO:133 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 175, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: one comprising the amino acid sequence of SEQ ID NO. 37, one of LC-CDR1An LC-CDR2 comprising the amino acid sequence SEQ ID NO:51 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:62 or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 175; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 175; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 175; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 134, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 134, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:134 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 134 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 176, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 176; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, oneA HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163 and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 176; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 176; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 135, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 135, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:135 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 135 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: HC-C comprising the amino acid sequence SEQ ID NO. 1DR1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 177, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 177; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 177; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 177; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some casesIn embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 136, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 136, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:136 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 136 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 178, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 178; v (V) L The V is L Comprising: one comprising the amino acid sequence of SEQ ID NO. 37 and one comprising the amino groupLC-CDR2 of the acid sequence SEQ ID NO. 51 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 178; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 178; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 137, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 137, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:137 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 137 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 179, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 179; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 179; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR2 comprisingHC-CDR3 of amino acid sequence SEQ ID NO. 179; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 138, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 138, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 138 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 138 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 180, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 180; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 180; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 180; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 139, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 139, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises a bagV comprising the amino acid sequence SEQ ID NO 139 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 139 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:191, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:191, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 191, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR2 comprising the amino acid sequenceLC-CDR3 of SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:191, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 140, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 140. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO:140 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:140 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CD comprising the amino acid sequence SEQ ID NO 192R1, a LC-CDR2 comprising the amino acid sequence SEQ ID NO:51 and a LC-CDR3 comprising the amino acid sequence SEQ ID NO:62 or V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:192, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:192, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:192, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151And V L The V is L Comprising the amino acid sequence SEQ ID NO. 141, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 141. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO. 141 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:141 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 193, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 193, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: comprising the amino acid sequence SEQ ID NO1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 193, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 193, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO:142, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 142. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO:142 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:142 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one comprising amino acidsHC-CDR1 of SEQ ID NO. 1, HC-CDR2 comprising amino acid sequence SEQ ID NO. 163 and HC-CDR3 comprising amino acid sequence SEQ ID NO. 182 or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:194, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: comprising the amino acid sequence SEQ ID NO. 194, a LC-CDR2 comprising the amino acid sequence SEQ ID No. 51, and a LC-CDR3 comprising the amino acid sequence SEQ ID No. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising amino acid sequence SEQ ID NO:194, an LC-CDR2 comprising amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising amino acid sequence SEQ ID NO:194, an LC-CDR2 comprising amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising amino acid sequence SEQ ID NO: 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 144, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 144. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO. 144 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-C of (2)DR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:144 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 195, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:195, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:195, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1 and one HC-CDR1 comprising the amino acid sequence SE HC-CDR2 of Q ID NO. 163, and HC-CDR3 comprising amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:195, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO:145, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 145. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO:145 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:145 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 196, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-cancer agentPsl antibodies include V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 196, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 196, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 196, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 146, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 146. At the position ofIn some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 151 H And V comprising the amino acid sequence SEQ ID NO 146 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:146 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 197, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 197, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: one comprising the amino acid sequence SEQ ID NO 197 and one comprising the amino acid sequence SEQLC-CDR2 of ID No. 51, and an LC-CDR3 comprising the amino acid sequence of SEQ ID No. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 197, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO:147, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO: 147. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO 147 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 147 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Included: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 36; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 132, or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97% >, a sequence which is identical to the amino acid sequence SEQ ID NO. 132, Variant sequences of 98% or 99%) sequence homology and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 132 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 132 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:198, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:198, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:198, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:198, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 148, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO. 148. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO. 148 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:148 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The saidV H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR comprising the amino acid sequence SEQ ID NO. 37LC-CDR3 of NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:149, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO:149, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:149 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO:149 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: bag(s)LC-CDR1 comprising amino acid sequence SEQ ID NO. 37, LC-CDR2 comprising amino acid sequence SEQ ID NO. 51, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 24; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 150, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 150, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 150 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising a polypeptide having the amino acid sequence SEQ ID NO. 150V H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: one comprising the amino acid sequence of SEQ ID NO. 1 HC-CDR1, one comprising ammoniaHC-CDR2 of the amino acid sequence SEQ ID NO. 163, and HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments of the present invention, in some embodiments,the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 152, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 152, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143.In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 152 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 152 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: one comprising the amino acid sequence SEQ ID NO. 50 and one comprising the amino acid sequence SEQLC-CDR2 of ID No. 51, and an LC-CDR3 comprising the amino acid sequence of SEQ ID No. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 164, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 183; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 153, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 153, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 153 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO 153 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps:an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 13, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 181; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:149, or comprising at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98) of the amino acid sequence SEQ ID NO:149% or 99%) sequence homology, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:149 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO:149 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 185, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 185; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Included: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 185; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 185; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 154, or comprising a variant sequence having at least 90% (e.g.at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 154, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 154 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 154 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 186, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 186; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 186; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 186; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 62, LC-CDR3.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO:155, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO:155, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 91, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:155 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO:155 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs:91 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 187, or a V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 187; v (V) L The V is L Comprising: one comprisesLC-CDR1 comprising amino acid sequence SEQ ID NO. 50, LC-CDR2 comprising amino acid sequence SEQ ID NO. 51, and LC-CDR3 comprising amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 187; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 187; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 156, or comprising variant sequences having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 156, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 156 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising a polypeptide having the amino acid sequence SEQ ID NO. 15V of 6 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 188, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 188; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 188; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a pack HC-CDR2 comprising amino acid sequence SEQ ID NO. 163, and HC-CDR3 comprising amino acid sequence SEQ ID NO. 188; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 50, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 62.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 157, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 157, and V L The V is L Comprising the amino acid sequence SEQ ID NO:143, or comprising a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO: 143. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:157 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 157 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising a V having the amino acid sequence SEQ ID NOs:143 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the following steps: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182, or V comprising up to 5 amino acid substitutions in the HC-CDRs H Variants; v (V) L The V is L Comprising the following steps: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 69, or a V comprising up to 5 amino acid substitutions in the LC-CDRs L Variants.
In some embodimentsIn one example, the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 69. In some embodiments, an anti-Psl antibody is provided that specifically competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 69. In some embodiments, an anti-Psl antibody that binds to the same epitope as an antibody comprising V is provided H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 163, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 182; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 37, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 51, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 69.
In some embodiments, the anti-Psl antibody comprises V H The V is H Comprising the amino acid sequence SEQ ID NO. 151, or comprising a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 151, and V L The V is L Comprising the amino acid sequence SEQ ID NO. 98, or comprising a variant having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 98A sequence of the body. In some embodiments, the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO 98 L . In some embodiments, the anti-Psl antibody comprises: v (V) H The V is H Comprising V having the amino acid sequence SEQ ID NO. 151 H HC-CDR1, HC-CDR2 and HC-CDR3; v (V) L The V is L Comprising V having the amino acid sequence SEQ ID NOs 98 L LC-CDR1, LC-CDR2 and LC-CDR3 of (a).
In some embodiments, competition experiments can be used to identify monoclonal antibodies that competitively bind to Psl with the anti-Psl antibodies described herein. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by one antibody competitively inhibiting the binding of the other antibody to the antigen. In certain embodiments, such a competing antibody binds to the same epitope as the antibodies described herein. Some exemplary competition experiments include, but are not limited to, routine experiments as mentioned in Harlow and Lane (1988) Antibodies A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, cold Spring Harbor, N.Y.). A detailed exemplary method for resolving epitopes bound by antibodies is described in Morris (1996), "Epitope Mapping Protocols," in Methods in Molecular Biology vol.66 (Humana Press, totowa, N.J.). In some embodiments, each antibody is said to bind to the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with the anti-Psl antibodies described herein is a chimeric, humanized or fully human antibody.
Exemplary anti-Psl antibody sequences are shown in tables 2 and 3, with the numbering of CDRs according to the EU index as in Kabat. Those skilled in the art will recognize that there are a variety of known algorithms to predict CDR positions and define antibody light and heavy chain variable regions. CDRs, V comprising an anti-Psl antibody as described herein H And/or V L Sequences, but based on predictive algorithms other than the antibodies exemplified in the tables below are also within the scope of the application.
TABLE 2 exemplary anti-Psl antibody CDR sequences
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TABLE 3 exemplary anti-Psl antibody mutant CDR sequences
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TABLE 4 exemplary anti-Psl antibody mutant CDR sequences
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TABLE 5 exemplary anti-Psl antibody V H And V L Sequence(s)
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Table 6 exemplary anti-Psl antibody mutant V H And V L Sequence(s)
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Table 7 exemplary sequences
Binding affinity
Binding affinity may be expressed using Kd, koff, kon or Ka. As used herein, the term "Koff" refers to the rate constant of dissociation of an antibody from an antigen/antibody complex, as determined by a kinetic selection device. The term "Kon" refers to the binding rate constant of an antibody to an antigen to form an antigen/antibody complex. As used herein, the dissociation constant "Kd" refers to the dissociation constant at which a particular antibody antigen interacts, and refers to the concentration of antigen required in an antibody molecule solution to occupy half of all antibody binding sites and reach equilibrium, equal to Koff/Kon. Determination of Kd assumes that all binding molecules are in solution. In the case of antibody attachment to the cell wall, for example in yeast expression systems, the corresponding dissociation rate constant is expressed as EC50, which is a good approximation of Kd. The affinity binding constant Ka is the inverse of the dissociation constant Kd.
Equilibrium dissociation constant (Kd) can be used as an indicator of the affinity of a reactive antibody moiety for an antigen. For example, the interactions between biomolecules can be analyzed by Scatchard method using antibodies labeled with various markers, and Biacore instrument (manufactured by Amersham Biosciences) by surface plasmon resonance according to a user manual or an attached kit. The Kd values obtained using these methods are expressed in units M. Antibodies that specifically bind to the target may have, for example, 10 +. -7 M、≤10 -8 M、≤10 -9 M、≤10 -10 M、≤10 -11 M、≤10 -12 M or less than or equal to 10 -13 Kd value of M.
The binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore assays, peptide scans, and the like.
In some embodiments, the anti-Psl antibody specifically binds to a Psl target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10 -7 M to 10 -13 M、10 -8 M to 10 -13 M、10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Thus, in some embodiments, the Kd value of the binding between the anti-Psl antibody and Psl is 10 -7 M to 10 -13 M、1×10 -7 M to 5X 10 -13 M、10 -7 M to 10 -12 M、10 -7 M to 10 -11 M、10 -7 M to 10 -10 M、10 -7 M to 10 -9 M、10 -8 M to 10 -13 M、1×10 -8 M to 5X 10 -13 M、10 -8 M to 10 -12 M、10 -8 M to 10 -11 M、10 -8 M to 10 -10 M、10 -8 M to 10 -9 M、5×10 -9 M to 1X 10 -13 M、5×10 -9 M to 1X 10 -12 M、5×10 -9 M to 1X 10 -11 M、5×10 -9 M to 1X 10 -10 M、10 -9 M to 10 -13 M、10 -9 M to 10 -12 M、10 -9 M to 10 -11 M、10 -9 M to 10 - 10 M、5×10 -10 M to 1X 10 -13 M、5×10 -10 M to 1X 10 -12 M、5×10 -10 M to 1X 10 -11 M、10 -10 M to 10 -13 M、1×10 -10 M to 5X 10 -13 M、1×10 -10 M to 1X 10 -12 M、1×10 -10 M to 5X 10 -12 M、1×10 -10 M to 1X 10 -11 M、10 - 11 M to 10 -13 M、1×10 -11 M to 5X 10 -13 M、10 -11 M to 10 -12 M、10 -12 M to 10 -13 M. In some embodiments, the Kd value of binding between the anti-Psl antibody and Psl is 10 -7 M to 10 -13 M。
In some embodiments, the Kd value of binding between the anti-Psl antibody and the non-target is higher than the Kd value of the anti-Psl antibody to the target, and in some embodiments cited herein, the binding affinity of the anti-Psl antibody to the target (e.g., psl) is higher than the binding affinity of the Psl antibody to the non-target. In some embodiments, non-target refers to a non-Psl antigen. In some embodiments, the anti-Psl antibody (directed against Psl) binds to a non-Psl target with a Kd value that is at least 10-fold, e.g., 10-100-fold, 100-1000-fold, 10-fold, greater than the Kd bound between the anti-Psl antibody and the target Psl 3 -10 4 Multiple of 10 4 -10 5 Multiple of 10 5 -10 6 Multiple of 10 6 -10 7 Multiple of 10 7 -10 8 Multiple of 10 8 -10 9 Multiple of 10 9 -10 10 Multiple of 10 10 -10 11 Multiple of 10 11 -10 12 Multiple times.
Nucleic acid
Nucleic acid molecules encoding anti-Psl antibodies are also contemplated. In some embodiments, a nucleic acid (or set of nucleic acids) encoding a full-length anti-Psl antibody is provided, including any of the full-length anti-Psl antibodies described herein. In some embodiments, a nucleic acid (or set of nucleic acids) of an anti-Psl antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, his-tag, HA tag).
Also contemplated herein are isolated host cells comprising an anti-Psl antibody, isolated nucleic acids encoding an anti-Psl antibody polypeptide component, or vectors comprising nucleic acids encoding an anti-Psl antibody polypeptide component described herein.
The application also includes variants of these nucleic acid sequences. For example, variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to nucleic acid sequences encoding anti-Psl antibodies of the application.
The application also provides vectors into which the nucleic acid sequences of the application can be inserted.
Briefly, a natural or synthetic nucleic acid encoding an anti-Psl antibody (e.g., a full length anti-Psl antibody) may be expressed by inserting the nucleic acid into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, including, for example, promoters (e.g., lymphocyte-specific promoters) and 3' untranslated regions (UTRs). The vectors may be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate the expression of a nucleic acid sequence of interest.
The nucleic acids of the application can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. nos.5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the application also provides gene therapy vectors.
Nucleic acids can be cloned into many types of vectors. For example, the nucleic acid may be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe-generating vectors and sequencing vectors.
In addition, the expression vector may be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York), as well as in other virology or molecular biology manuals. Viruses that may be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses. In general, suitable vectors include an origin of replication, promoter sequences, convenient restriction endonuclease sites, and one or more selectable markers that function in at least one organism (see, e.g., WO 01/96584
01/29058; and U.S. Pat. No.6,326,193).
Many virus-based systems have been developed for transferring genes into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene may be inserted into a vector and packaged into retroviral particles using techniques known in the art. The recombinant virus is then isolated and delivered to cells of the subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, an adenovirus vector is used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Retroviral-derived vectors, such as lentiviruses, are suitable tools for achieving long-term gene transfer, as they allow for long-term stable integration of the transgene and propagation in daughter cells. Lentiviral vectors have additional advantages over retroviruses derived from tumors, such as the mouse leukemia virus, in that they can transduce non-dividing cells, such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
Other promoter elements, e.g., enhancers, regulate the transcription initiation frequency. Typically they are located 30-110bp upstream of the start site, although many promoters have recently been found to contain functional elements downstream of the start site as well. The spacing between promoter elements is generally flexible so that the function of the promoter is maintained when the elements are interchanged or moved in position relative to each other. In the thymidine kinase (tk) promoter, the spacing between promoter elements increases to 50bp and the activity begins to decrease.
One example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. The promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operably linked thereto. Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter. However, other constitutive promoters may also be used, including, but not limited to, simian virus 40 (SV 40) early promoter, mouse Mammary Tumor Virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, moMuLV promoter, avian leukemia virus promoter, epstein-Barr virus immediate early promoter, rous sarcoma virus promoter, and human gene promoters including, for example, but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. Furthermore, the application should not be limited to the use of constitutive promoters only. Inducible promoters are also contemplated by the present application. The use of an inducible promoter provides a molecular switch that enables expression of the polynucleotide sequence to which it is operably linked when such expression is desired and turns off expression when not desired. Inducible promoters, including but not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
In some embodiments, expression of the anti-Psl antibody is inducible. In some embodiments, the nucleic acid sequence encoding the anti-Psl antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
Inducible promoter
The use of an inducible promoter provides a molecular switch that can initiate expression of a polynucleotide sequence operably linked thereto when expression is desired and which can shut down expression when expression is not desired. Exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone-modulating elements (see, e.g., mader, S.and White, J.H. (1993) Proc.Natl. Acad. Sci. USA 90:5603-5607), synthetic ligand-modulating elements (see Spencer, D.M.et al (1993) Science 262:1019-1024), and ionizing radiation-modulating elements (see Manome, Y.et al (1993) Biochemistry 32:10607-10613;Datta,R.et al) (1992) Proc.Natl. Acad. Sci. USA 89:1014-10153). Other exemplary inducible promoters suitable for use in mammalian systems in vivo or in vitro are described in Gingrich et al (1998) Annual Rev. Neurosci 21:377-405. In some embodiments, the inducible promoter system for expression of the anti-Psl antibody is the Tet system. In some embodiments, the inducible promoter system for expression of the anti-Psl antibody is the e.
One exemplary inducible promoter system employed in the present application is the Tet system. The system is based on the Tet system described by golden et al (1993). In one exemplary embodiment, the target polynucleotide is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription of the promoter. In the activated state, for example, in the presence of an inducer such as tetracycline (Tc), anhydrous tetracycline, doxycycline (Dox), or an active analog thereof, the inducer will release TetR from TetO, resulting in transcription. Doxycycline is a member of the tetracycline antibiotic family under the chemical name 1-dimethylamino-2, 4a,5, 7-pentahydroxy-11-methyl-4, 6-dioxo-1, 4a,11 a,12 a-hexahydrotetraene-3-carboxamide.
In one embodiment, tetR is codon optimized for expression in mammalian cells, such as mouse or human cells. Because of the degeneracy of the genetic code, most amino acids are encoded by more than one codon, such that the sequence of a given nucleic acid has a large number of variants without any change in the amino acid sequence encoded thereby. However, many organisms differ in codon usage, also known as "codon preference" (i.e., the preference of a given amino acid to use a particular codon). Codon preference is generally related to the presence of dominant tRNA species for a particular codon, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a particular species (e.g., prokaryotes) can thus be tailored by codon optimization to enhance their expression in a different species (e.g., eukaryotes).
Other specific variations of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactive in the presence of Tc or Dox. In this system, the tetracycline-regulated transcriptional activator protein (tTA), consisting of TetR fused to the strong transcriptional activation domain of the herpes simplex virus VP16, regulates expression of the target nucleic acid under the transcriptional control of the tetracycline responsive promoter element (TRE). The TRE element consists of a TetO sequence tandem fused to a promoter (typically the smallest promoter sequence derived from the human cytomegalovirus immediate early promoter). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.
In contrast, in the Tet-On system, transcription is active in the presence of Tc or Dox. The Tet-On system is based On the reverse tetracycline regulated transcriptional activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and VP16 transactivation domain. However, a 4 amino acid change in the DNA binding region of TetR alters the binding properties of rtTA such that it recognizes only the tetO sequence on the target transgenic TRE in the presence of Dox. Therefore in the Tet-On system rtTA activates the transcription of the target gene regulated by TRE only in the presence of Dox.
Another inducible promoter system is the E.coli lac repressor system (see Brown et al, cell49:603-612 (1987)). The Lac repressor system functions by regulating transcription of a polynucleotide of interest operably linked to a promoter comprising the Lac operator (lacO). Lac repressors (lacR) bind to LacO and thereby prevent transcription of the target polynucleotide. Expression of the polynucleotide of interest is induced by a suitable inducer, for example isopropyl- β -D thiogalactopyranoside (IPTG).
To assess the expression of the polypeptide or portion thereof, the expression vector to be introduced into the cell may further comprise a selectable marker gene or a reporter gene or both to facilitate identification and selection of the expressing cell from a population of cells transfected or infected with the viral vector. In other aspects, the selectable marker may be carried on separate DNA fragments and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene may be flanked by appropriate regulatory sequences to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like.
Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences. Typically, a reporter gene is a gene that is not present in or expressed by a recipient organism or tissue, and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cell, the expression of the reporter gene is detected at an appropriate time. Suitable reporter genes may include genes encoding luciferases, beta-galactosidases, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or green fluorescent protein (e.g., ui-Tel et al, 2000FEBS Letters 479:79-82). Suitable expression systems are well known and may be prepared by known techniques or obtained commercially. In general, constructs with minimal 5' flanking regions that show the highest expression level of the reporter gene are considered promoters. Such promoter regions may be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
In some embodiments, nucleic acids encoding any of the full-length anti-Psl antibodies described herein are provided. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding a full length anti-Psl antibody heavy and light chain. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector may be selected from, for example, mammalian expression vectors and viral vectors (such as vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, the vector may be readily introduced into a host cell, such as a mammalian cell, bacterial, yeast or insect cell, by any method known in the art. For example, the expression vector may be introduced into the host cell by physical, chemical or biological means.
Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, gene gun methods, microinjection, electroporation, and the like. Methods for preparing cells comprising vectors and/or exogenous nucleic acids are well known in the art. See, e.g., green and Sambrook (2013,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York). In some embodiments, the polynucleotide is introduced into the host cell by calcium phosphate transfection.
Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, adeno-associated viruses, and the like. See, e.g., U.S. Pat. nos.5,350,674 and 5,585,362.
Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems, such as macromolecular complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).
In the case of non-viral delivery systems, an exemplary delivery vehicle is a liposome. The use of lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo or in vivo) is contemplated. In another aspect, the nucleic acid may be conjugated to a lipid. The lipid-bound nucleic acid may be entrapped within the aqueous interior of the liposome, dispersed within the lipid bilayer of the liposome, linked to the liposome by a linking molecule that binds to the liposome and the oligonucleotide, entrapped in the liposome, formed a complex with the liposome, dispersed in a solution containing the lipid, mixed with the lipid, bound to the lipid, suspended in the lipid, contained in or mixed with the micelle, or otherwise bound to the lipid. The lipid, lipid/DNA or lipid/expression vector-related composition is not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles, or in a "collapsed" structure. They may also be simply dispersed in solution, possibly forming aggregates of non-uniform size or shape. Lipids are fatty substances, which may be naturally occurring or synthetic. For example, lipids include fat droplets naturally occurring in the cytoplasm, as well as a class of compounds containing long chain aliphatic hydrocarbons and derivatives thereof, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
Regardless of the method used to introduce exogenous nucleic acid into a host cell or otherwise expose the cell to the inhibitors of the application, various experiments can be performed in order to confirm the presence of the recombinant DNA sequence in the host cell. Such assays include, for example, "molecular biology" assays well known to those of skill in the art. Such as Southern and Northern blotting, RT-PCR and PCR; "biochemical" assays, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by the assays described herein, are within the scope of the application.
Preparation of anti-Psl antibodies
In some embodiments, the anti-Psl antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-Psl antibody comprises V from a monoclonal antibody H And V L Or a variant thereof. In some embodiments, the anti-Psl antibody further comprises C from a monoclonal antibody H 1 and C L A region, or a variant thereof. Monoclonal antibodies can be prepared using methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods, for example. Furthermore, exemplary phage display methods are described herein and in the examples below.
In hybridoma cell methods, hamsters, mice, or other suitable host animals are typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, lymphocytes may be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the protein of interest. Typically, peripheral Blood Lymphocytes (PBLs) are used if human cells are desired, whereas spleen cells or lymph node cells are used if non-human mammalian cells are desired. Lymphocytes are fused with an immortalized cell line, such as polyethylene glycol, using an appropriate fusion agent to form a hybridoma cell. Immortalized cell lines are typically transformed mammalian cells, especially myeloma cells of rodent, bovine and human origin. Rat or mouse myeloma cell lines are typically used. The hybridoma cells may be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of the unfused immortalized cells. For example, if the parent cell lacks hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT), the hybridoma cell culture medium typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents HGPRT-deficient cells from growing.
In some embodiments, the immortalized cell lines fuse efficiently, ensure high levels of stable expression of antibodies by the antibody-producing cell of choice, and are sensitive to certain media, such as HAT media. In some embodiments, the immortal cell line is a mouse myeloma cell line, available from, for example, the sork cell collection in san diego, california and the american type culture collection in ma, virginia. Human myeloma and murine-human hybrid myeloma cell lines are also described for use in the production of humanized monoclonal antibodies.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, such as Radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of a monoclonal antibody can be determined by, for example, the Scatchard (Scatchard) assay described in Munson and Pollard, anal. Biochem.,107:220 (1980).
After the desired hybridoma cells are identified, the target clone may be subcloned by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle Medium (DMEM) and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown as ascites in a mammalian body.
Monoclonal antibodies secreted by subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification methods, such as protein A-sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
In some embodiments, according to any of the anti-Psl antibodies described herein, the anti-Psl antibody comprises a sequence selected from a clone of an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clones may be identified by screening combinatorial libraries of antibody fragments having the desired activity. For example, a variety of methods are known in the art for generating phage display libraries and screening these libraries to obtain antibodies of the desired binding characteristics. These methods are reviewed in, for example, hoogenboom et al, methods in Molecular Biology 178:178:1-37 (O' Brien et al, ed., human Press, totowa, N.J., 2001), and in, for example, mcCafferty et al, nature 348:552-554;
clackson et al, nature 352:624-628 (1991); marks et al, J.mol. Biol.222:581-597 (1992); marks and Bradbury, methods in Molecular Biology 248:161-175 (Lo, ed., human Press, totowa, n.j., 2003); sidhu et al, J.mol. Biol.338 (2): 299-310 (2004); lee et al, J.mol.biol.340 (5): 1073-1093 (2004); felloose, proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al, J.Immunol. Methods 284 (1-2): 119-132 (2004).
In some phage display methods, V is cloned separately by Polymerase Chain Reaction (PCR) H And V L All components of the gene are randomly recombined in a phage library and then screened for phages capable of binding antigen as described in Winter et al, ann.rev.immunol.,12:433-455 (1994). Phage typically display antibody fragments as scFv fragments or as Fab fragments. The immune-derived library phage provides high affinity antibodies to the immunogen without the need to construct hybridoma cells. Alternatively, natural libraries can be cloned (e.g., toFrom humans) to provide a single source of antibodies against multiple non-self and self antigens without any immunization, as described in Griffiths et al, EMBO J,12:725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and encoding CDR3 hypervariable regions using PCR primers comprising random sequences and completing the rearrangement in vitro, as described in Hoogenboom and Winter, J.mol.biol.,227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Pat. nos. 5,750,373, and US Patent Publication nos. 2005/007974, 2005/019455, 2005/0266000, 2007/017126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
The anti-Psl antibodies are prepared by phage display screening of the anti-Psl antibody portion of the library that is capable of specifically binding to the target Psl. The library may be a human scFv phage display library having at least 1X 10 9 (e.g. at least 1X 10) 9 、2.5×10 9 、5×10 9 、7.5×10 9 、1×10 10 、2.5×10 10 、5×10 10 、7.5×10 10 Or 1X 10 11 ) A diverse variety of unique human antibody fragments. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs and spleen of healthy subjects, comprising all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library in which the heavy chain CDR3 is entirely random, with all amino acids (except cysteine) present at any given position with the same probability. (see, e.g., hoet, R.M. et al, nat. Biotechnol.23 (3): 344-348, 2005). In some embodiments, the heavy chain CDR3 of the semi-synthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids in length. In some embodiments, the library is a fully synthetic phage display library. In one place In some embodiments, the library is a non-human phage display library.
Phage clones with high affinity for the target Psl may be screened by iterative binding of phage to the target Psl, which is bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. The bound phage clones are then eluted and used to infect appropriate host cells, e.g., E.coli XL1-Blue, for expression and purification. Phage clones that specifically bind Psl can be enriched by multiple rounds of panning (e.g., 2, 3, 4, 5, 6 or more rounds), such as solution panning, cell panning, or both. Specific binding of the enriched phage clones to the target Psl can be detected by any method known in the art, including, for example, ELISA and FACS.
Another method of screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al (U.S. Pat. Nos.6,699,658 and 6,696,251) developed a method for displaying libraries of yeast cells. In such yeast display systems, one component includes a yeast lectin protein (Aga 1), which is immobilized on the yeast cell wall. Another component includes the second subunit of lectin protein Aga2, which can be displayed on the yeast cell surface by disulfide bonds with the Aga1 protein. After the Aga1 gene integration, the protein Aga1 is expressed from the yeast chromosome. A library of single chain variable fragments (scFv) was genetically fused to the Aga2 sequence in a yeast display plasmid, which was maintained in yeast by a nutritional marker exon after transformation. Both the Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.
The human antibody V gene lineages (VH and VK fragments) were obtained by PCR methods using a set of degenerate primers, (Sblattero, D. & Bradbury, a.immunotechnology 3,271-278 1998). PCR templates are from RNAs or cDNAs on the market, including PBMC, spleen, lymph nodes, bone marrow and tonsils. Independent VH and VK PCR libraries were pooled together and then assembled together by overlap extension PCR to form the scFv format (Sheets, m.d.et al proc.Natl. Acad.sci.usa 95,6157-6162 1998). To construct a yeast scFv display library, the generated scFv PCR products were cloned into a yeast display plasmid by homologous recombination. (Chao, G, et al, nat Protoc.2006;1 (2): 755-68.Miller KD,et al.Current Protocols in Cytometry 4.7.1-4.7.30,2008).
anti-Psl antibodies can be found using a mammalian cell display system in which the antibody portion is displayed on the cell surface and specific antibodies against the target Psl are isolated by antigen-directed screening methods, as described in U.S. patent No.7,732,195B2. A Chinese Hamster Ovary (CHO) cell bank can be established representing a large number of human IgG antibody genes and used to discover clones expressing high affinity antibody genes. Another display system has been developed that allows simultaneous display and secretion of the same protein on the cell surface by alternative splicing, wherein the displayed protein phenotype remains genotype-dependent, allowing simultaneous characterization of soluble secreted antibodies in biophysical and cell-based functional assays. This approach overcomes many of the limitations previously exhibited by mammalian cells and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgG (Peter M.Bowers, et al Methods 2014, 65:44-56). Transient expression systems are suitable for single round antigen selection prior to restoring antibody genes and are therefore most useful for selecting antibodies from smaller libraries. Stable exon vectors offer an attractive option. The exon vectors can be transfected efficiently and stably maintain low copy numbers, allowing multiple rounds of panning and solving more complex antibody libraries.
The IgG library is based on V gene fragments of germline sequences isolated from a set of human donors linked to a rearranged (D) J region. RNA collected from 2000 human blood samples was reverse transcribed into cDNA using V H And V K Specific primer amplification V H And V K Fragments were purified by gel extraction. By combining V H And V K Fragments were subcloned into display vectors containing the IgG1 or K constant regions, respectively, and then electroporated or transduced into 293T cells to prepare IgG libraries. To prepare scFv antibody display libraries, the scFv antibodies are displayed by ligation V H And V K Production of scFvs and subcloning into display vectorIn vivo, the vector is then electroporated or transduced into 293T cells. As far as we know, the IgG repertoire is based on the ligation of germline sequence V gene segments with rearranged (D) J regions, isolated from a panel of donors, which may be mice, rats, rabbits or monkeys.
Monoclonal antibodies can also be prepared by recombinant DNA methods, for example as described in U.S. patent No.4, 816,567. The DNA encoding the monoclonal antibodies of the application can be readily isolated and sequenced by conventional methods, such as by oligonucleotide probes that specifically bind to the light and heavy chain genes encoding murine antibodies. The hybridoma cells described above or the Psl-specific phage clones of the application may serve as a source of such DNA. After isolation, the DNA may be placed in an expression vector, which is then transfected into a host cell, such as simian COS cells, chinese hamster ovary Cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain monoclonal antibodies synthesized in the recombinant host cell. The DNA may also be modified, for example, by replacing homologous non-human sequences with coding sequences for human heavy and light chain constant structure and/or framework regions (U.S. patent No.4,816,567;Morrison et al, supra), or by covalently linking all or part of the coding sequence of a non-immunoglobulin polypeptide to an immunoglobulin coding sequence. Such non-immunoglobulin polypeptides may replace the constant regions of the antibodies of the application, or may replace one of the antigen binding sites in the variable domains of the antibodies of the application, to form chimeric bivalent antibodies.
The antibody may be a monovalent antibody. Methods of making monovalent antibodies are known in the art. For example, a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain. Heavy chains are typically truncated at any position in the Fc region to prevent heavy chains from cross-linking with each other. Alternatively, the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
In vitro methods are also suitable for the preparation of monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, may be accomplished using any method known in the art.
The antibody variable domain having the desired binding specificity (antibody-antigen binding site) may be fused to an immunoglobulin constant region. Preferably fusion with an immunoglobulin heavy chain constant region, which comprises at least part of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH 1) comprising the necessary site for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, and if desired, the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
Fully human and humanized antibodies
The anti-Psl antibody (e.g., full length anti-Psl antibody) may be a humanized antibody or a fully human antibody. Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., fv, fab, fab ', F (ab') 2 Other antigen binding subsequences of scFv or antibodies), which typically include minimal sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which residues from a recipient CDR are replaced by non-human (donor antibody) CDR residues having the desired specificity, affinity and properties, such as mouse, rat or rabbit CDRs. In some embodiments, the human immunoglobulin Fv framework region residues are replaced by corresponding non-human residues. Humanized antibodies may also comprise amino acid residues that are neither of the recipient antibody nor in the introduced CDR or framework sequences. Typically, a humanized antibody comprises at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin consensus sequences.
Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "import" residues, typically from "import" variable domains. According to some embodiments, humanization may be performed essentially as described below by Winter and colleagues (Jones et al, nature,321:522-525 (1986); riechmann et al, nature,332:323-327 (1988); verhoeyen et al, science,239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Thus, this "humanized" antibody portion (U.S. patent No.4,816,567), which is substantially less than a fully human antibody, has its variable domains replaced by corresponding sequences from a non-human source. In practice, humanized antibody portions are typical human antibody portions in which some CDR residues and possibly some framework region residues are replaced with residues from similar sites in rodent antibodies.
Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) that are capable of producing a complete fully human antibody library after immunization without endogenous immunoglobulin production can now be prepared. For example, homozygous deletion of the antibody heavy chain Junction (JH) gene in chimeric and germ-line mutant mice has been reported to completely suppress endogenous antibody production. Transfer of an array of human germline immunoglobulin genes into such germline mutant mice can produce fully human antibodies under antigen stimulation, see, e.g., akobovits et al, PNAS USA,90:2551 (1993); jakobovits et al, nature,362:255-258 (1993); bruggemann et al, year in immunol.,7:33 (1993); U.S. patent nos.5,545,806,5,569,825,5,591,669;5,545,807; and WO 97/17852. Alternatively, fully human antibodies can be prepared by introducing a human immunoglobulin locus into a transgenic animal (e.g., a mouse in which endogenous immunoglobulin genes have been partially or fully silenced). Upon antigen stimulation, the production of fully human antibodies can be found to be very similar in all respects to their production in humans, including gene rearrangement, assembly and antibody libraries. Such methods are described, for example, in U.S. patent nos.5,545,807;5,545,806;5,569,825;5,625,126;5,633,425; and 5,661,016,and Marks et al, bio/Technology,10:779-783 (1992); lonberg et al, nature,368:856-859 (1994); morrison, nature,368:812-813 (1994); fishwild et al Nature Biotechnology,14:845-851 (1996); neuberger, nature Biotechnology,14:826 (1996); lonberg and Huszar, international.Rev.Immunol., 13:65-93 (1995).
Fully human antibodies have also been generated by in vitro activation of B cells (see U.S. patent 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J.mol.biol.,227:381 (1991); the techniques of Marks et al, J.mol.biol.,222:581 (1991), cole et al, and Boerner et al can also be used to prepare fully human monoclonal antibodies. See Cole et al, monoclonal Antibodies and Cancer Therapy, alan R.Lists, p.77 (1985) and Boerner et al, J.Immunol.,147 (1): 86-95 (1991).
anti-Psl antibody variants
In some embodiments, the amino acid sequences of anti-Psl antibody variants provided herein (e.g., full length anti-Psl antibodies) are also contemplated. For example, it may be desirable to improve the binding affinity and/or other biological activity of antibodies. The amino acid sequence of an antibody variant may be prepared by introducing appropriate modifications in the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the amino acid sequence of the antibody. The final construction can be accomplished by any combination of amino acid residue deletions, insertions, and substitutions to impart the desired characteristics. For example, antigen binding.
In some embodiments, anti-Psl antibody variants having one or more amino acid substitutions are provided. Target sites for substitution mutations include hypervariable regions (HVRs) and Framework Regions (FRs). Amino acid substitutions may be introduced into the antibody of interest to screen for products of a desired activity, e.g., improved biological activity, retention/improvement of antigen binding capacity, reduced immunogenicity, or improved opsonophagocytic killing (OPK) of pathogenic bacteria, e.g., pseudomonas aeruginosa. Conservative substitutions are shown in table 8 below.
TABLE 8 conservative substitutions
Original residue Exemplary substitution Preferably substituted
Ala(A) Val；Leu；Ile Val
Arg(R) Lys；Gln；Asn Lys
Asn(N) Gln；His；Asp,Lys；Arg Gln
Asp(D) Glu；Asn Glu
Cys(C) Ser；Ala Ser
Gln(Q) Asn；Glu Asn
Glu(E) Asp；Gln Asp
Gly(G) Ala Ala
His(H) Asn；Gln；Lys；Arg Arg
Ile(I) Leu；Val；Met；Ala；Phe；Norleucine Leu
Leu(L) Norleucine；Ile；Val；Met；Ala；Phe Ile
Lys(K) Arg；Gln；Asn Arg
Met(M) Leu；Phe；Ile Leu
Phe(F) Trp；Leu；Val；Ile；Ala；Tyr Tyr
Pro(P) Ala Ala
Ser(S) Thr Thr
Thr(T) Val；Ser Ser
Trp(W) Tyr；Phe Tyr
Tyr(Y) Trp；Phe；Thr；Ser Phe
Val(V) Ile；Leu；Met；Phe；Ala；Norleucine Leu
Amino acids are classified into different classes according to the nature of the side chain:
hydrophobic amino acid: norleucine, methionine Met, alanine Ala, valine Val, leucine Leu, isoleucine Ile;
neutral hydrophilic amino acid: cysteine Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln;
acidic amino acid: aspartic acid Asp, glutamic acid Glu;
basic amino acid: histidine His, lysine Lys, arginine Arg;
amino acids affecting the chain direction: glycine Gly, proline Pro;
aromatic amino acid: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
Substitutions of non-conservative amino acids include substitution of one of the above classes into another class.
One exemplary substitution variant is an affinity matured antibody, conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibody portion displayed on phage, and variants are screened for specific biological activity (e.g., based on RBC cell lysis inhibition assays or binding affinities). Changes (e.g., substitutions) may be made in the HVRs region to obtain improved RBC-based inhibition assays or antibody affinities. Changes can be made in the "hot spot" of the HVR, i.e., codon-encoded residues that undergo high frequency mutations during somatic maturation (see, e.g., chordhury, methods mol. Biol).
207:179-196 (2008)), and/or at Specific Determinant Residues (SDRs), detecting the resulting variant V H And V L Is used for the binding affinity of (a) to the substrate. Methods of constructing and reselecting affinity maturation from secondary libraries have been described in several documents, for example, hoogenboom et al in Methods in Molecular Biology 178:1-37 (O' Brien et al ed., human Press, totowa, N.J. (2001)).
In some affinity maturation embodiments, diversity is introduced into the selected variable genes for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another approach to introducing diversity involves HVR-mediated approaches in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 regions are generally particularly important targets.
In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the ability of the antibody to bind to an antigen. For example, conservative changes (e.g., conservative substitutions provided herein) may be made in HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot spot" or SDRs region. In some embodiments, the variant VH and VL sequences provided above, each HVR is either unchanged or comprises no more than 1, 2, or 3 amino acid substitutions.
One useful method by which amino acid residues or regions of an antibody can be identified that can be targeted for mutation is termed "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid) are substituted with neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the interaction of the antibody with the antigen is affected. Substitutions may be further introduced at the amino acid position to demonstrate functional sensitivity of the position to the initial substitution. Alternatively or additionally, the contact site between the antibody and the antigen is identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues may be targeted or eliminated as substitution candidates. Variants are screened to determine if they have the desired properties.
Insertion of amino acid sequences, including fusion at the amino and/or carboxy terminus, ranges in length from 1 residue to polypeptides comprising 100 or more residues, and also includes insertion of 1 or more amino acid residues within the sequence. Examples of terminal insertions include antibodies having a methionyl residue at the N-terminus. Other insertional variants of antibody molecules include polypeptides that fuse an enzyme (e.g., ADEPT) or increase the serum half-life of an antibody at the N-or C-terminus of the antibody molecule.
Variant Fc region
In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full length anti-Psl antibody or an anti-Psl antibody fusion protein), thereby producing an Fc region variant. In some embodiments, the Fc region variant has enhanced ADCC potency, typically associated with Fc-binding receptors (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of alterations or mutations in Fc sequences affecting their potency, for example, WO 00/42072 and Shields et al J biol. Chem.9 (2): 6591-6604 (2001) describe antibody variants with increased or decreased binding to FcRs. The contents of these publications are incorporated herein by reference.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in which effector cells of the immune system actively lyse target cells (e.g., infected cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-Psl antibodies). Typically ADCC effects involve NK cells activated by antibodies. NK cells express the Fc receptor CD16. The receptor recognizes and binds to the Fc portion of an antibody molecule that binds to the surface of a target cell. The most common Fc receptor on the surface of NK cells is CD16 or fcyriii. Binding of the Fc receptor to the Fc region of the antibody results in activation of NK cells, release of the cell lysis particles, and subsequent apoptosis of the target cells.
In some embodiments, the application also provides anti-Psl antibody variants (e.g., full length anti-Psl antibody variants) comprising an Fc region having one or more effector functions, such as CDC or ADCC. Among the major cells mediating ADCC, NK cells express fcyriii only, whereas monocytes express fcyri, fcyrii and fcyriii. The expression of FcR on hematopoietic cells is summarized in Table 3 at page 464 of Ravetch and Kinet Annu.Rev.Immunol.9:457-492 (1991). Non-limiting examples of in vitro evaluation of ADCC activity of a target molecule are described in U.S. Pat. No.5,500,362 (see, e.g., hellstrom, I.et al Proc.Nat 'l Acad.Sci.USA 83:7059-7063 (1986)) and Hellstrom, I.et al, proc.Nat' l Acad.Sci.USA 82:1499-1502 (1985); U.S. Pat. No.5,821,337 (see Bruggemann, M.et al., J.Exp. Med.166:1351-1361 (1987)). Alternatively, non-radioactive detection methods (see, e.g., ACTI TM Flow cytometry non-radioactive cytotoxicity assays (CellTechnology, inc.Mountain View, calif.) and CYTOTOX 96 TM Nonradioactive cytotoxicity assay (Promega, madison, wis.). Effector cells employed in such assay experiments include Peripheral Blood Mononuclear Cells (PBMCs) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule is detected in vivo, for example, in an animal model, as described in Clynes et al Proc.Nat' l Acad.Sci.USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody is unable to bind to C1q, thereby lacking CDC activity. See, e.g., C1q and C3C binding ELISA in WO2006/029879 and WO 2005/100402. To assess complement activation, CDC assays can be performed (see, e.g., gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996); cragg, M.S. et al, blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life are determined using methods known in the art (see, e.g., petkova, s.b. et al, int' l.immunol.18 (12): 1759-1769 (2006)).
Antibodies with reduced effector function comprising substitution of one or more residues at residues 238, 265, 269, 270, 297, 327 and 329 of the Fc region (u.s.pat.no. 6,737,056). These Fc variants include Fc variants with substitution of two or more residues at positions 265, 269, 270, 297 and 327, including Fc variants known as "DANA" with substitution of alanine at residues 265 and 297 (u.s.pat. No.7,332, 581).
Such antibody variants with increased or decreased binding to FcRs have been described (see, e.g., U.S. Pat.No.6,737,056; WO 2004/056312, and Shields et al, J.biol.chem.9 (2): 6591-6604 (2001)).
In some embodiments, the change in the Fc region results in a change in conditioning (i.e., an increase or decrease), as described in Moore et al, MAbs.2 (2): 181-189 (2010).
In some embodiments, an anti-Psl antibody (e.g., full length anti-Psl antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions that is capable of extending half-life and/or enhancing binding to an Fc receptor (FcRn). Antibodies with extended half-life and improved FcRn binding are described in US2005/0014934A1 (hiton et al). These antibody Fc regions comprise one or more amino acid substitutions that enhance the binding of the Fc region to FcRn. These Fc variants comprise one or more substitutions in residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434 in the Fc region, for example a substitution in residue 434 in the Fc region (u.s.pat. No.7,371,826).
See also Duncan & Winter, nature 322:738-40 (1988); U.S. Pat. nos. 5,648,260; examples of other Fc region variants are provided in U.S. Pat. No.5,624,821 and WO 94/29351.
The application contemplates anti-Psl antibodies (e.g., full length anti-Psl antibodies) comprising any one or a combination of the Fc variants described herein.
Glycosylation variants
In some embodiments, an anti-Psl antibody provided herein (e.g., a full length anti-Psl antibody) is altered to increase or decrease the degree of glycosylation of the anti-Psl antibody. The addition or deletion of glycosylation sites on anti-Psl antibodies can be conveniently accomplished by altering the amino acid sequence of the anti-Psl antibody or polypeptide portion thereof to thereby add or remove one or more glycosylation sites.
Wherein the anti-Psl antibody comprises an Fc region to which a saccharide can be altered. Natural antibodies produced by mammalian cells typically comprise branched double-antennary oligosaccharides, which are typically linked to the Fc region CH2 domain Asn297 via an N-linkage, see, e.g., wright et al, TIBTECH 15:26-32 (1997). The oligosaccharides may comprise a variety of sugars, such as mannose, N-acetylglucosaminide (GlcNAc), galactose and sialic acid, as well as trehalose attached to the GlcNAc of the "stem" of the double-antennary oligosaccharide structure. In some embodiments, the anti-Psl antibodies of the application may be oligosaccharide modified to produce anti-Psl antibody variants with certain improved properties.
N-glycans attached to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al, J.biochem.2006,140:777-83. Typically, a small fraction of naturally occurring nonfucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to fcγr; whereas non-fucosylated N-glycans enhance the binding capacity of Fc to fcγriiia. Enhanced binding to fcγriiia results in enhanced ADCC effects, which is advantageous in certain antibody therapeutic applications where cytotoxicity is required.
In some embodiments, enhanced effector function may be detrimental when Fc-mediated cellular cytotoxicity is not required. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
In some embodiments, anti-Psl antibody (e.g., full length anti-Psl antibody) variants are provided that comprise an Fc region, wherein the saccharide structure linked to the Fc region has reduced fucose or lacks fucose, which may enhance ADCC function. In particular, provided herein are anti-Psl antibodies having reduced fucose relative to the same anti-Psl antibodies produced by wild type CHO cells. That is, they are characterized by having a smaller amount of fucose than antibodies produced by natural CHO cells (e.g., CHO cells producing a naturally glycosylated form, CHO cells containing the natural FUT8 gene). In some embodiments, the N-linked glycans of the anti-Psl antibodies have less than 50%, 40%, 30%, 20%, 10%, or 5% fucose. For example, the anti-Psl antibody may have a fucose content of 1% -80%, 1% -65%, 5% -65% or 20% -40%. In some embodiments, the N-linked glycans of the anti-Psl antibodies do not comprise fucose, i.e., wherein the anti-Psl antibodies are completely free of fucose, or are free of fucose or are defucosylated. The fucose content is determined by calculating the average fucose content in the sugar chains attached to Asn297 relative to the total amount of all sugar structures attached to Asn297 (e.g. complex, hybrid or mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546. Asn297 refers to the asparagine residue at position 297 of the Fc region (EU Fc region residue numbering system). However, asn297 may also be located upstream or downstream of position 297 by ±3 amino acids, i.e. between positions 294 and 300, due to minor sequence variations of the antibody. These fucosylated variants may have enhanced ADCC function. See, for example, US Patent Publication nos. US 2003/0157108 (Presta, l.), US 2004/0093621 (Kyowa Hakko Kogyo co., ltd). Examples of publications related to antibody variants that are "defucosylated" or "lack of fucose" include US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/015614; US 2002/0164328; US 2004/0093621; US 2004/013321; US 2004/010704; US (US)
2004/0110282；US 2004/0109865；WO 2003/085119；WO 2003/084570；WO 2005/035586；WO 2005/035778；WO2005/053742；WO2002/031140；Okazaki et al.J.Mol.Biol.
336:1239-1249 (2004); yamane-Ohnuki et al Biotech.Bioeng.87:614 (2004). Cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking the fucosylation function of the protein (Ripka et al, arch. Biochem. Biophysis. 249:533-545 (1986), US Pat Appl No US 2003/0157108 A1,Presta,L, and WO 2004/056312 A1,Adams et al, especially example 11), and knockout cell lines, such as alpha-1, 6-fucosyltransferase genes, FUT8 knockout CHO cells (see Yamane-Ohnuki et al, biotech. Bioeng.87:614 (2004), kanda, y. Et al, biotechnol. Bioeng.,94 (4): 680-688 (2006), and WO 2003/085107).
Variants of anti-Psl antibodies (e.g., full length anti-Psl antibodies) further provide bisected oligosaccharides, e.g., wherein a double-antennary oligosaccharide linked to the Fc region of an anti-Psl antibody is bisected by GlcNAc. Such anti-Psl antibody (e.g., full length anti-Psl antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are described in WO 2003/011878 (Jean-mair et al); U.S. Pat. No.6,602,684 (Umana et al); US (US)
2005/0123346 (Umana et al), and Ferrara et al, biotechnology and Bioengineering,93 (5): 851-861 (2006). Also provided are variants of anti-Psl antibodies (e.g., full length anti-Psl antibodies) having at least one galactose residue in the oligosaccharide linked to the Fc region. Such anti-Psl antibody variants may have enhanced CDC function. Such variants are described, for example, in WO 1997/30087 (Patel et al); WO 1998/58964 (Raju, s.); and WO 1999/22764 (Raju, S.).
In some embodiments, the anti-Psl antibody (e.g., full length anti-Psl antibody) variant comprises an Fc region capable of binding to fcyriii. In some embodiments, the anti-Psl antibody (e.g., full length anti-Psl antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or has enhanced ADCC activity in the presence of human effector cells as compared to an otherwise identical anti-Psl antibody (e.g., full length anti-Psl antibody) having a human wild-type IgG1 Fc region.
Cysteine engineered variants
In some embodiments, it is desirable to prepare a cysteine engineered anti-Psl antibody (e.g., a full length anti-Psl antibody) in which one or more amino acid residues are substituted with cysteine residues. In some embodiments, the substitution residue occurs at an accessible site of the anti-Psl antibody. By substituting those residues with cysteines, active sulfhydryl groups located at accessible sites of anti-Psl antibodies can be used to couple the anti-Psl antibodies with other moieties, such as drug moieties or linker-drug moieties, to prepare anti-Psl immunoconjugates as further described herein. Cysteine engineered anti-Psl antibodies (e.g., full length anti-Psl antibodies) may be prepared as described, for example, in U.S. Pat. No.7,521,541.
Derivatives and their use as inhibitors of viral infection
In some embodiments, the anti-Psl antibodies provided herein (e.g., full length anti-Psl antibodies) can be further modified to include other non-protein portions known and readily available in the art. Moieties suitable for derivatizing anti-Psl antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyaminoacids (homo-or random copolymers), dextran or poly (n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, propylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerin), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the anti-Psl antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the amount and/or type of polymer used for derivatization may be determined based on considerations including, but not limited to, the need to improve the properties or function of the anti-Psl antibody, whether the anti-Psl antibody derivative is used for treatment under particular conditions, and the like.
In some embodiments, conjugates of anti-Psl antibodies (e.g., full length anti-Psl antibodies) with non-protein moieties are provided, possibly heated selectively by exposure to radiation. In some embodiments, the non-protein moiety is a carbon nanotube (Kam et al, proc.Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may be of any wavelength, including but not limited to a wavelength that does not harm normal cells, but at which the non-protein moiety may be heated to a temperature that kills cells proximal to the anti-Psl antibody non-protein moiety conjugate.
Pharmaceutical composition
Also provided herein are compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any one of the anti-Psl antibodies (e.g., full length anti-Psl antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. In some embodiments, a pharmaceutical composition is provided comprising any of the anti-Psl antibodies described herein and a pharmaceutically acceptable carrier.
Suitable anti-Psl antibody formulations may be prepared in lyophilized or liquid formulation form by mixing an anti-Psl antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed. (1980)). Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as: phosphates, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl p-hydroxybenzoates such as methyl or propyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol); a low molecular weight (less than 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants such as TWEEN TM ，PLURONICS TM Or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418 and are expressly incorporated herein by reference. Lyophilized formulations suitable for subcutaneous administration are described in WO 97/04801. Such lyophilized formulationsThe high protein concentration formulation may be reconstituted by a suitable diluent and the reconstituted formulation may be administered to the individual to be treated herein by subcutaneous administration. Cationic liposomes or liposomes can be used to deliver the anti-Psl antibodies of the application to cells.
The formulations described herein may contain, in addition to an anti-Psl antibody (e.g., a full length anti-Psl antibody), one or more other active agents necessary to treat a particular disorder, preferably agents that are complementary in activity and do not adversely react with each other. For example, it may be desirable to further include an anti-neoplastic agent, a growth inhibitor, a cytotoxic agent or a chemotherapeutic agent in addition to the anti-Psl antibody. These molecules are present in combination in amounts effective for the intended purpose. The effective amount of these other substances depends on the amount of anti-Psl antibody in the formulation, the type of disease or disorder or treatment, and other factors as described above. These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of the presently employed dosages.
The anti-Psl antibodies (e.g., full length anti-Psl antibodies) may also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Can be prepared into sustained release preparation.
Sustained release formulations of anti-Psl antibodies (e.g., full length anti-Psl antibodies) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragments thereof), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactic acid (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and ethyl L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprorelin acetate) and poly-D (-) -3-hydroxybutyric acid. Although the following are providedHowever, polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can allow release of molecules for more than 100 days, and certain hydrogels can release proteins in a shorter time. When encapsulated antibodies stay in the body for a long period of time, they may denature or aggregate as a result of exposure to a humid environment at 37 ℃ and may result in loss of biological activity or altered immunogenicity. anti-Psl antibodies can be stabilized according to corresponding mechanisms, rationalized strategies. For example, if the aggregation mechanism is found to be the formation of intermolecular S-S bonds through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.
In some embodiments, the anti-Psl antibody (e.g., full length anti-Psl antibody) is formulated in a buffer containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (tween 80), or any combination thereof. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising about 100mM to about 150mM glycine. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising about 50mM to about 100mM NaCl. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising about 10mM to about 50mM acetate. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising about 10mM to about 50mM succinic acid. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising about 0.005% to about 0.02% polysorbate 80. In some embodiments, the anti-Psl antibody is formulated in a buffer having a pH between 5.1 and 5.6. In some embodiments, the anti-Psl antibody is formulated in a buffer comprising 10mM citric acid, 100mM NaCl, 100mM glycine, and 0.01% polysorbate 80, wherein the pH of the formulation is 5.5.
Formulations for in vivo administration must be sterile. This can be easily achieved by, for example, filtration using sterile filtration membranes.
Therapeutic or prophylactic methods using anti-Psl antibodies
In certain embodiments, a method of treating a pseudomonas infection in a subject is provided, the method comprising administering to the subject an effective amount of a composition comprising any one of the anti-Psl antibodies described herein. In some embodiments, the method of treating a pseudomonas infection further provides a therapeutic or prophylactic effect on a disease and/or disorder associated with a pseudomonas infection. In certain aspects, a method of preventing a pseudomonas infection in a subject is provided, comprising administering to the subject an effective amount of a composition comprising any one of the anti-Psl antibodies described herein. In some embodiments, the use of an anti-Psl antibody (any of the anti-Psl antibodies described above) or a pharmaceutical composition (any of the pharmaceutical compositions described above comprising an anti-Psl antibody) in the manufacture of a medicament for treating a disease or disorder.
Diseases and/or conditions associated with pseudomonas infection include, but are not limited to, fever, chills, fatigue, muscle and joint pain, joint swelling, headache, diarrhea, rash, wound pus, bacteremia, acute pneumonia, intraperitoneal infection. Further exemplary diseases include, but are not limited to, respiratory tract infections, bacteremia, septic shock, suppurative arthritis, enteritis, skin soft tissue infections (e.g., burn wound infections), urinary tract infections, intestinal tract infections, ulcerative keratitis, chronic suppurative otitis media, mastoiditis, sinusitis, and endocarditis. In some embodiments, the method of treating or preventing a pseudomonas infection reduces mortality caused by the pseudomonas infection.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, a HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23, and a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34; v (V) L The V is L Comprising: an LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 38-39, 41-49, an LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 52-53, 55-61, and an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75. In some casesIn one embodiment, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, a HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23, and a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34; v (V) L The V is L Comprising: an LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 38-39, 41-49, an LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 52-53, 55-61, and an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 2-3, 5-12, a HC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 14-15, 17-23, and a HC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 25-26, 28-34; v (V) L The V is L Comprising: an LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs 38-39, 41-49, an LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs 52-53, 55-61, and an LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs 63-64, 66-68, 70-75.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90 and 159; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97 and 99-104. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is providedA method comprising administering to an individual an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90 and 159; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97 and 99-104. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising any one of the amino acid sequences of SEQ ID NOs 80-81, 83-90 and 159; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 92-93, 95-97 and 99-104.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: one LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, one LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and oneAnd an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO 80 H V comprising the amino acid sequence SEQ ID NO. 92 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:80 H V comprising the amino acid sequence SEQ ID NO. 92 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 38, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 63, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 80, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID No. 80; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 92, or a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 92.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 64. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 64.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO. 81 H V comprising the amino acid sequence SEQ ID NO:93 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:81 H V comprising the amino acid sequence SEQ ID NO:93 L 。
In some implementationsIn an embodiment, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 39, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 53, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 64, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO. 81, or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to the amino acid sequence SEQ ID NO. 81; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 93, or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 93.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, whereinThe anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:83 H V comprising the amino acid sequence SEQ ID NO 95 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:83 H V comprising the amino acid sequence SEQ ID NO 95 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO 159 H V comprising the amino acid sequence SEQ ID NO 95 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:159 H V comprising the amino acid sequence SEQ ID NO 95 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject With an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 5, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 17, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 28, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 41, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 66, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO. 83, or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology to the amino acid sequence SEQ ID NO. 83; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 95, or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 95. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO 159 or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to the amino acid sequence SEQ ID NO 159; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 95, or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 95.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18,and an HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO 84 H V comprising the amino acid sequence SEQ ID NO:96 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO 84 H V comprising the amino acid sequence SEQ ID NO:96 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO. 6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO. 18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO. 29,or a variant comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 42, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 55, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 67, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO. 84, or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO. 84; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 96, or a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 96.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25; v (V) L The V is L Comprising: one comprising the amino acid sequence SEQ ID NO. 43 LC-CDR1, oneAn LC-CDR2 comprising the amino acid sequence SEQ ID NO:56 and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 68.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:85 H V comprising the amino acid sequence SEQ ID NO 97 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:85 H V comprising the amino acid sequence SEQ ID NO 97 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 7, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 14, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 25, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 43, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 56, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 68, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 85, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID No. 85; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 97 or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence with the amino acid sequence SEQ ID NO. 97Variant sequences of homology.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO 86 H V comprising the amino acid sequence SEQ ID NO 99 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:86 H V comprising the amino acid sequence SEQ ID NO 99 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 8, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 19, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 30, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 44, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 57, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 70, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 86, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID No. 86; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 99, or a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 99.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subjectWith an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO. 81 H V comprising the amino acid sequence SEQ ID NO. 100 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:81 H V comprising the amino acid sequence SEQ ID NO. 100 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 3, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 15, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 26, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 45, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 58, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 71, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO. 81, or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to the amino acid sequence SEQ ID NO. 81; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 100, or a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 100.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising a polypeptide comprising an amino acidV of the base acid sequence SEQ ID NO. 87 H V comprising the amino acid sequence SEQ ID NO. 101 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:87 H V comprising the amino acid sequence SEQ ID NO. 101 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 9, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 20, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 31, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 46, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 52, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 72, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 87, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID No. 87; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 101, or a variant sequence having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 101.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 10, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 21, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 32; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO. 88 H V comprising the amino acid sequence SEQ ID NO. 102 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO 88 H V comprising the amino acid sequence SEQ ID NO. 102 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: one HC-CDR1 comprising the amino acid sequence SEQ ID NO 10 and one HC-CDR1 comprising the amino acid sequence SEQ ID NO:21, and an HC-CDR3 comprising the amino acid sequence SEQ ID No. 32, or a variant comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 47, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 73, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID NO. 88, or having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence homology with the amino acid sequence SEQ ID NO. 88; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 102, or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 102.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:89 H V comprising the amino acid sequence SEQ ID NO. 103 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:89 H V comprising the amino acid sequence SEQ ID NO. 103 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 11, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 22, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 33, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 48, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 74, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 89, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID No. 89; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 103 or having at least 90% (e.g.to)Variant sequences with 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% less sequence homology.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75. In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO 90 H V comprising the amino acid sequence SEQ ID NO 104 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising an amino acid sequenceV of SEQ ID NO. 90 H V comprising the amino acid sequence SEQ ID NO 104 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V H The V is H Comprising: a HC-CDR1 comprising the amino acid sequence SEQ ID NO. 12, a HC-CDR2 comprising the amino acid sequence SEQ ID NO. 23, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO. 34, or variants comprising up to 5 amino acid substitutions; v (V) L The V is L Comprising: an LC-CDR1 comprising the amino acid sequence SEQ ID NO. 49, an LC-CDR2 comprising the amino acid sequence SEQ ID NO. 61, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO. 75, or variants comprising up to 5 amino acid substitutions. In some embodiments, the anti-Psl antibody comprises V H The V is H A variant sequence comprising the amino acid sequence SEQ ID No. 90, or having at least 90% (e.g. at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology to the amino acid sequence SEQ ID No. 90; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 104, or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence homology with the amino acid sequence SEQ ID NO. 104.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises a heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising IHSVH (SEQ ID NO: 4), or a variant thereof comprising up to 3 amino acid substitutions; one HC-CDR2 comprising TIISSGTTTTYAQSFQD (SEQ ID NO: 16), or a variant thereof comprising up to 3 amino acid substitutions; and an HC-CDR3 comprising X 1 X 2 X 3 X 4 (SEQ ID NO: 189), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 D, Y or N, X 2 Is G or A, X 3 Is D or T, X 4 S, A or T; light chain variable domain (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQGISSWLA (SEQ ID NO: 40), or a variant thereof comprising up to 3 amino acid substitutions; an LC-CDR2 comprising HASTLES (SEQ ID NO: 54), or a variant thereof comprising up to 3 amino acid substitutions; and an LC-CDR3 comprising LQAX 1 SLPTH (SEQ ID NO: 158), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, D, Y, F, P, G, K, H, A, C, E, Q, R, S, T, V, W or L.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises a heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising IHSVH (SEQ ID NO: 4), a HC-CDR2 comprising TIISSGTTTTYAQSFQD (SEQ ID NO: 16) and a HC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:35, SEQ ID NOs: 165-169; light chain variable domain (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQGISSWLA (SEQ ID NO: 40), a LC-CDR2 comprising HASTRES (SEQ ID NO: 54) and a LC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:65, SEQ ID NOs:76-78, SEQ ID NOs: 199-212.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:82 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:82 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, a method ofA method of treating or preventing a pseudomonas infection in a subject, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID No. 82 H And V comprising the amino acid sequence SEQ ID NO. 94 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises a V comprising the amino acid sequence of any one of SEQ ID NOs 105-110 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NOs 105-110 H And V comprising the amino acid sequence SEQ ID NO. 94 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NOs 105-110 H And V comprising the amino acid sequence SEQ ID NO. 94 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:82 H And V comprising the amino acid sequence of any one of SEQ ID NOs:111-127 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:82 H And V comprising the amino acid sequence of any one of SEQ ID NOs:111-127 L . In some embodimentsIn another aspect, a method is provided for treating or preventing a Pseudomonas infection in a subject, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:82 H And V comprising the amino acid sequence of any one of SEQ ID NOs:111-127 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO. 113 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:107 H And V comprising the amino acid sequence SEQ ID NO. 113 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:107 H And V comprising the amino acid sequence SEQ ID NO. 113 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO. 123 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:107 H And V comprising the amino acid sequence SEQ ID NO. 123 L . In some embodiments, a treatment or pre-treatment is providedA method of preventing a pseudomonas infection in an individual comprising administering to the individual an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID No. 107 H And V comprising the amino acid sequence SEQ ID NO. 123 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO 107 H And V comprising the amino acid sequence SEQ ID NO. 116 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:107 H And V comprising the amino acid sequence SEQ ID NO. 116 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:107 H And V comprising the amino acid sequence SEQ ID NO. 116 L 。
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising SSGDYWG (SEQ ID NO: 1), or a variant thereof comprising up to 3 amino acid substitutions; comprising SIHNX 1 GSTYYNPSLKG (SEQ ID NO: 213), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 S, K or Q; and one containing QFGSETYYX 1 GIX 2 HC-CDR3 of P (SEQ ID NO: 190), or variants thereof comprising up to 3 amino acid substitutions, wherein X 1 N, S, V, T or P, X 2 D, Y, C is a,H. S, R, A, E, G, K, W, V or Q; light chain variable domain (V L ) The V is L Comprising the following steps: comprising RSSQSLLHSX 1 Light chain complementarity determining region (LC-CDR) 1 of GYNYLD (SEQ ID NO: 184), or a variant thereof comprising up to 3 amino acid substitutions, wherein X 1 N, A, V, F, R, G, H, Q, W or P; an LC-CDR2 comprising lgsnas (SEQ ID NO: 51), or a variant thereof comprising up to 3 amino acid substitutions; and one containing MQALQTPX 1 LC-CDR3 of T (SEQ ID NO: 214), wherein X 1 Is R or Y, or a variant thereof comprising up to 3 amino acid substitutions.
In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises: heavy chain variable domain (V H ) The V is H Comprising the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising SSGDYWG (SEQ ID NO: 1); an HC-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO 13, SEQ ID NOs 163-164; and a HC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 24, SEQ ID NO. 36, SEQ ID NOs 170-183, SEQ ID NOs 185-188; light chain variable domain (V L ) The V is L Comprising the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO. 37, SEQ ID NO. 50, SEQ ID NOs 191-198; an LC-CDR2 comprising LGSNRAS (SEQ ID NO: 51); and an LC-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:62, SEQ ID NO: 69.
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:79 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO:79 H Sum bagV comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO:79 H And V comprising the amino acid sequence SEQ ID NO 91 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided, comprising administering to a subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises a V comprising the amino acid sequence of any one of SEQ ID NOs 128-139, 149-151, 154-155 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NOs 128-139, SEQ ID NOs 149-151, SEQ ID NOs 154-155 H And V comprising the amino acid sequence SEQ ID NO 91 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NOs 128-139, SEQ ID NOs 149-151, 154-155 H And V comprising the amino acid sequence SEQ ID NO 91 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided, comprising administering to a subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO:151 H And V comprising the amino acid sequence of any one of SEQ ID NOs 140-148 L . In some embodiments, a method of treating or preventing a pseudomonas infection in a subject is provided, comprisingAdministering to the individual an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO. 151 H And V comprising the amino acid sequence of any one of SEQ ID NOs 140-148 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence of any one of SEQ ID NOs 140-148 L 。
In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided, comprising administering to a subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody comprises V comprising an amino acid sequence of any one of SEQ ID NO:132, SEQ ID NO:149, SEQ ID NOs:152-153, SEQ ID NOs:156-157 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NO. 132, SEQ ID NO. 149, SEQ ID NOs 152-153, SEQ ID NOs 156-157 H And V comprising the amino acid sequence SEQ ID NO:143 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds the same epitope as an antibody comprising V comprising an amino acid sequence of any one of SEQ ID NO:132, SEQ ID NO:149, SEQ ID NOs:152-153, SEQ ID NOs:156-157 H And V comprising the amino acid sequence SEQ ID NO:143 L 。
In some embodiments, there is provided a method of treating or preventing a pseudomonas infection in a subject, comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibodyWherein said anti-Psl antibody comprises V comprising the amino acid sequence SEQ ID NO. 151 H And V comprising the amino acid sequence SEQ ID NO. 98 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody competes with an antibody comprising V comprising the amino acid sequence SEQ ID NO. 151 H And V comprising the amino acid sequence SEQ ID NO. 98 L . In some embodiments, a method of treating or preventing a Pseudomonas infection in a subject is provided comprising administering to the subject an effective amount of a composition comprising an anti-Psl antibody, wherein the anti-Psl antibody binds to the same epitope as an antibody comprising V comprising the amino acid sequence SEQ ID NO 151 H And V comprising the amino acid sequence SEQ ID NO. 98 L 。
In some embodiments, the anti-Psl antibodies comprise an antibody heavy chain constant region and an antibody light chain constant region, in any of the methods of treatment or prophylaxis described herein. In some embodiments, the anti-Psl antibody comprises an IgG1 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG2 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG3 type heavy chain constant region. In some embodiments, the anti-Psl antibody comprises an IgG4 type heavy chain constant region. In some embodiments, the IgG refers to human IgG. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 160. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 161. In some embodiments, the anti-Psl antibody comprises a lambda light chain constant region. In some embodiments, the anti-Psl antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO. 162. In some embodiments, the anti-Psl antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
In some embodiments, any of the methods of treatment or prophylaxis described herein further provide a therapeutic or prophylactic effect on a disease and/or disorder associated with a pseudomonas infection. In some embodiments, the methods can prevent pseudomonas infection in an individual.
In some embodiments, the individual is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, a laboratory animal, or the like. In some embodiments, the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old). In some embodiments, the individual is older than 60 years (including, for example, older than 70, 80, 90, or 100 years).
In some embodiments, the individual is present with one or more risk factors associated with a pseudomonas aeruginosa infection. For example, in some embodiments, the individual has exposed or damaged a skin mucus layer. In some embodiments, the individual has one or more burns. In some embodiments, the individual has one or more surgical wounds. In some embodiments, the individual has a skin disorder. In some embodiments, the individual has a foreign body implant, such as, but not limited to, a respirator or catheter. In some embodiments, the individual is diagnosed with or is genetically predisposed to an immunodeficiency disorder, including but not limited to HIV infection, AIDS, and/or neutropenia. In some embodiments, the subject has received one or more forms of chemotherapy. In some embodiments, the individual is treated with one or more forms of adrenoglucocorticoid. In some embodiments, the subject has received one or more forms of chemotherapy. In some embodiments, the individual is diagnosed with or is genetically predisposed to cancer, diabetes, and/or chronic structural lung disease (e.g., cystic fibrosis or COPD). In some embodiments, the individual is diagnosed with or is genetically predisposed to a dysbacteriosis of the digestive system and/or other organs. In some embodiments, the individual has one or more risk factors associated with one or more of the diseases or conditions described above.
In some embodiments, the application provides a method of delivering an anti-Psl antibody (such as any of the anti-Psl antibodies described herein, e.g., an isolated anti-Psl antibody) to a cell infected with a pathogen in an individual, the method comprising administering to the individual a composition comprising the anti-Psl antibody.
In some embodiments, according to any of the methods described herein, the method further comprises administering one or more additional therapeutic agents. In some embodiments, the at least one therapeutic agent is an antibiotic. In some embodiments, the antibiotic is a penicillin, a cephalosporin, a carbapenem, a fluoroquinolone, an aminoglycoside, a monoamine bacterium, a polymyxin, an antibiotic composition comprising a β -lactamase inhibitor, or any combination thereof. In some embodiments, the antibiotic is cefepime, ceftazidime, cefpirome, imipenem, meropenem, ticarcillin, piperacillin, azlocillin, carboxillin, mezlocillin, atranan, tobramycin, gentamicin, amikacin, ciprofloxacin, levofloxacin, cefpirome sulbactam, piperacillin-tazobactam, fosfomycin, or any combination thereof. In some embodiments, the antibiotic is one or more of imipenem, tobramycin, ciprofloxacin, meropenem, or a Qu Nazhong. In some embodiments, the antibiotic is one or more of gentamicin, ampicillin, or kanamycin.
Diagnostic methods for infectious pathogens expressing Psl and clinical descriptions of these diseases are known in the art. Such methods include, but are not limited to, for example, immunohistochemistry, PCR, and Fluorescence In Situ Hybridization (FISH).
In some embodiments, the anti-Psl antibodies (e.g., full length anti-Psl antibodies) and/or compositions are used in combination with a second, third, or fourth agent (including, e.g., an antibiotic) to treat or prevent a disease or disorder associated with a Psl expressing pathogen.
Dosage and method of administration of anti-Psl antibodies
The dosage of the anti-Psl antibody (e.g., isolated anti-Psl antibody) composition administered to an individual (e.g., human) may vary with the particular composition, mode of administration, and type of disease being treated. In some embodiments, the amount of the composition (e.g., a composition comprising an isolated anti-Psl antibody) is effective to produce an objective response (e.g., a partial response or a complete response) in the treatment or prevention of a pseudomonas infection. In some embodiments, the amount of the anti-Psl antibody composition is sufficient to produce a complete response in the individual. In some embodiments, the amount of the anti-Psl antibody composition is sufficient to produce a partial response in the individual. In some embodiments, the dose of the anti-Psl antibody composition administered (e.g., when administered alone) is sufficient to produce a total response rate of greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% in a population of individuals treated with the anti-Psl antibody composition. The response of an individual to a therapeutic or prophylactic method described herein can be determined, for example, by detection of pseudomonas using gram stain or other phenotypic testing methods.
In some embodiments, the amount of the composition (e.g., a composition comprising an isolated anti-Psl antibody) is sufficient to extend the progression free survival of the individual. In some embodiments, the amount of the composition is sufficient to extend the overall survival of the individual. In some embodiments, the amount of the composition (e.g., when administered alone) is sufficient to produce a clinical benefit of greater than 50%, 60%, 70%, or 77% in a population of individuals treated with the anti-Psl antibody composition.
In some embodiments, the amount of the composition (e.g., a composition comprising an isolated anti-Psl antibody), alone or in combination with a second, third, and/or fourth agent, is sufficient to reduce the organ load of pseudomonas by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the organ load of the same subject prior to treatment or compared to the corresponding organ load of other subjects not receiving treatment. The magnitude of the therapeutic effect can be measured using standard methods, such as in vitro assays for purified enzymes, cell-based assays, animal models, or human trials.
In some embodiments, when the composition is administered to an individual, the amount of anti-Psl antibody (e.g., full length anti-Psl antibody) in the composition is below a level that causes a toxic effect (i.e., an effect above a clinically acceptable toxicity level) or at a level where potential side effects can be controlled or tolerated.
In some embodiments, the amount of the composition approaches the Maximum Tolerated Dose (MTD) of the composition following the same dosing regimen. In some embodiments, the amount of the composition is greater than 80%, 90%, 95% or 98% of the MTD.
In some embodiments, the amount of anti-Psl antibody (e.g., full length anti-Psl antibody) in the composition is in the range of 0.001 μg to 1000 μg.
In some embodiments, the composition or method further comprises one or more antibiotics. In some embodiments, the antibiotic (e.g., imipenem, tobramycin, ciprofloxacin, meropenem, atran, ticarcillin, piperacillin, azlocillin, carbenicillin, meloxicam, gentamicin, or amikacin) is present in the composition in an amount in the range of 0.001 μg to 1000 μg.
In any of the embodiments described above, the effective amount of Psl antibody (e.g., full length anti-Psl antibody) in the composition is in the range of 0.1 μg/kg to 100mg/kg as calculated by body weight.
In any of the embodiments described above, the effective amount of the antibiotic (e.g., imipenem, tobramycin, ciprofloxacin, meropenem, atran, ticarcillin, piperacillin, azlocillin, carbenicillin, mezlocillin, gentamicin, or amikacin) in the composition is in the range of 0.1 μg/kg to 100mg/kg, calculated on a weight basis.
The anti-Psl antibody composition may be administered to a subject (e.g., a human) by a variety of routes including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalational, intravascular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, mucosal, or transdermal. In some embodiments, a slow release formulation of the composition is used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered via the portal vein. In some embodiments, the composition is administered through an artery. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intrahepatially. In some embodiments, the composition is administered by hepatic arterial infusion. In some embodiments, the composition is applied to a site remote from the first lesion.
Product and kit
In some embodiments of the application, an article of manufacture is provided that comprises a substance that is capable of being used to treat or prevent a pseudomonas infection in an individual, or to deliver an anti-Psl antibody (e.g., a full length anti-Psl antibody) into cells that are attached by a Psl expressing pathogen. The article of manufacture may comprise a container and a label or package insert attached to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be made of a variety of materials, such as glass or plastic. Typically, the container contains a composition effective to treat the diseases or conditions described herein and has a sterile port (e.g., the container may be an iv bag or a vial with a pierceable cap of a hypodermic injection needle). At least one active substance in the composition is the anti-Psl antibody. The label or package insert identifies the particular condition for which the composition may be used. The label or package insert further comprises instructions for administering the anti-Psl antibody composition to the patient. Articles of manufacture and kits comprising combination therapies are within the contemplation herein.
Package insert refers to instructions that are typically contained within the commercial package of therapeutic products, including indications, usage, dosage, administration, contraindications, and/or warning information regarding the use of such therapeutic products. In some embodiments, the package insert indicates that the composition may be used to treat a bacterial infection. In some embodiments, the package insert indicates that the composition is useful for treating pseudomonas infection.
In addition, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, grignard solution, or dextrose solution. Other materials may be included as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
Kits useful for various purposes are also provided, such as for treating or preventing a Pseudomonas infection in an individual, or for delivering an anti-Psl antibody (e.g., a full length anti-Psl antibody) to cells attached by Psl expressing pathogenic bacteria, optionally in combination with a preparation. Kits of the application include one or more containers comprising an anti-Psl antibody composition (or single dose form and/or article of manufacture), and in some embodiments, further comprising another agent (e.g., an agent described herein) and/or instructions for use consistent with any of the methods described herein. The kit may further comprise a description of the selection of suitable individuals for treatment. The instructions for use attached to the kits of the application are typically written instructions on labels or packaging instructions (e.g., paper sheets contained within the kit), and machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) are also acceptable.
For example, in some embodiments, the kit comprises a composition comprising an anti-Psl antibody (e.g., a full length anti-Psl antibody). In some embodiments, the kit comprises: a) A composition comprising any of the anti-Psl antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-Psl antibody. In some embodiments, the kit comprises: a) A composition comprising any one of the anti-Psl antibodies described herein, and b) instructions for administering the anti-Psl antibody composition to a subject for treating a pseudomonas infection in the subject. In some embodiments, the kit comprises: a) a composition comprising any one of the anti-Psl antibodies described herein, and b) at least one additional agent in an amount effective to enhance the effect (e.g., therapeutic effect, detection effect) of the anti-Psl antibody, and c) instructions for administering the anti-Psl antibody composition and additional agents to an individual for treating a pseudomonas infection in the individual. The anti-Psl antibody and the other substance may be present in separate containers or in the same container. For example, the kit may comprise one specific composition or two or more compositions, wherein one composition comprises an anti-Psl antibody and the other composition comprises another agent.
In some embodiments, the kit comprises a nucleic acid (or a set of nucleic acids) encoding an anti-Psl antibody (e.g., a full length anti-Psl antibody). In some embodiments, the kit comprises: a) A host cell (or set of nucleic acids) encoding an anti-Psl antibody, and b) an expression nucleic acid (or set of nucleic acids). In some embodiments, the kit comprises: a) A nucleic acid (or set of nucleic acids) encoding an anti-Psl antibody, and b) instructions for use, adapted to: i) Expressing an anti-Psl antibody in a host cell, ii) preparing a composition comprising the anti-Psl antibody, and iii) administering the composition comprising the anti-Psl antibody to the individual to treat or prevent a pseudomonas infection in the individual. In some embodiments, the kit comprises: a) a nucleic acid (or set of nucleic acids) encoding an anti-Psl antibody, b) a host cell expressing the nucleic acid (or set of nucleic acids), and c) instructions for use, adapted to: i) Expressing an anti-Psl antibody in a host cell, ii) preparing a composition comprising the anti-Psl antibody, and iii) administering the composition comprising the anti-Psl antibody to the individual to treat or prevent a pseudomonas infection in the individual.
The kit of the application is packaged in a suitable form. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packages (e.g., sealed mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and instructional information. Thus, the present application also provides articles of manufacture including vials (e.g., sealed vials), bottles, jars, flexible packaging, and the like.
Instructions for use of the anti-Psl antibody composition typically include information such as dosage, period of administration, and route of administration. The container may be unit dose, large package (e.g., multi-dose package) or subunit dose. For example, a kit comprising a sufficient dose of an anti-Psl antibody as described herein (e.g., full length anti-Psl antibody) is provided for long term effective treatment of an individual, e.g., one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit may also contain multiple unit doses of the anti-Psl antibody, pharmaceutical compositions, and instructions for use, and be packaged in amounts sufficient for storage and use in a pharmacy, such as a hospital pharmacy and a compound pharmacy.
Those skilled in the art will recognize several embodiments that are possible within the scope and spirit of the application. The application will now be described in more detail by reference to the following non-limiting examples. The following examples further illustrate the application but should not be construed as in any way limiting its scope.
Detailed Description
Example 1: preparation of Psl polysaccharide and screening of Single chain antibodies (scFv) against Psl
Preparation of Psl polysaccharide
The method for preparing the Psl polysaccharide comprises the following steps: pseudomonas aeruginosa PAO1 bacteria (CNCTC PAO 1) were inoculated onto LBNS (LB medium without NaCl), cultured at 37℃for 18 hours, the bacteria were collected and centrifuged, and the supernatant was discarded. After the bacteria are resuspended and precipitated, the bacterial biofilm is separated from the thalli by vibration or ultrasound. After centrifugation, ethanol was added to the supernatant to precipitate the polysaccharide. After high speed centrifugation, the pellet was resuspended and then treated with DNase I and proteinase K. Subsequently, the proteins were extracted and removed with phenol/chloroform, then the Psl polysaccharide was precipitated with ethanol and dissolved with water.
Preparation of biotinylated Psl polysaccharide
Using EZ-link according to manufacturer's instructions TM alkoxyamine-PEG-biotin reagent (Semerle technology) biotinylation of Psl polysaccharide was performed. Briefly, the polysaccharide is oxidized with sodium periodate, and after the reaction, the sodium periodate is removed by dialysis. Alkoxyamine-biotin was added to the oxidized Psl polysaccharide in a molar ratio of 1:9, followed by incubation at room temperature for 2 hours; finally, the biotinylated Psl polysaccharide is separated from the unreacted material by dialysis or desalting.
Screening for Single chain antibodies (scFv) against Psl
Construction of a yeast scFv antibody display library: RNAs were collected from 2000 human blood samples, cDNA was obtained by reverse transcription, and V H -and V K -specificitySexual primer amplification V H And V K Fragments. After gel extraction and purification, V is connected by a linker H And V K scFv was generated. These scFvs were cloned into the yeast display plasmid PYD1 and then electroporated into yeast to construct a yeast scFv antibody display library.
Screening for single chain antibodies against Psl: after several rounds of panning, scFvs recognizing Psl were enriched and screened from the yeast display library. Briefly, cells expressing anti-Psl scFv antibodies were enriched using magnetic bead sorting (MACS). Biotinylated Psl was combined with magnetic beads (Dynabeads according to manufacturer's instructions TM MyOne TM Strepitavidin T1) was mixed overnight to allow biotinylated Psl to coat the magnetic beads. The scFv antibody yeast library was then mixed with Psl coated magnetic beads, enriched for yeasts displaying Psl antibodies, unbound was washed away in the elution step. The enriched yeast samples from MACS panning were then subjected to Fluorescence Activated Cell Sorting (FACS). FACS-mediated screening was repeated for 2-3 cycles. The screened yeast pool cells were placed on agar, single colonies were picked and subjected to further FACS analysis. The scFv gene was extracted from Psl-binding positive yeast clones, fused to a 6-His tag, and subcloned into a prokaryotic expression vector. Subsequently, his-tagged scFvs were purified using the nickel column described above according to the manufacturer's instructions. After completion of the screening, a set of positive scFv antibodies were obtained and tested for their ability to inhibit adsorption of a549 cells by pseudomonas Aeruginosa (ATT) and promote opsonophagocytic killing (OPK).
Example 2: preparation and characterization of full-length human anti-Psl antibodies
Preparation of full-length human anti-Psl antibodies
The most potential scFv antibodies were reconstituted into human IgG1 antibody molecules having a heavy chain constant region of human IgG1 and a human kappa light chain constant region. Amplification of V from prokaryotic expression vectors L And V H Then constructed into eukaryotic expression vectors pTT5-L (comprising kappa constant region) and pTT5-H1 (comprising IgG1 heavy chain constant region), respectively. Extraction of plasmids expressing light chain or heavy chain, cotransfection of 293F cells, 37℃and 8% CO 2 The culture was carried out at 120rpm for 5 days, and the antibodies in the culture were purified by using Protein A affinity chromatography column.
Briefly, the Protein A column was first equilibrated with 6 column volumes of 50mM PBS buffer (pH 7.2) containing 0.15M NaCl at a flow rate of 150 cm/h. The culture supernatant (pH adjusted to 7.2) was passed through the column at a flow rate of 150 cm/h. After further equilibration, the eluate containing anti-Psl antibody was collected using 50mM sodium citrate buffer (ph 3.5). Full length IgG1 antibodies were evaluated for in vivo and in vitro biological activity. In vitro functional screening methods include opsonophagocytic killing (OPK) assays and cell (epithelial cell line a 549) adsorption assays. Endotoxin removal was performed on antibodies used in vivo experiments to reduce the effect of endotoxin on experimental results.
anti-Psl antibodies inhibit the adsorption of pseudomonas aeruginosa to a549 human lung epithelial cells
This experiment shows that anti-Psl antibodies inhibit the binding of pseudomonas aeruginosa to epithelial cells. For example (Choi K H, et al mini-Tn7 insertion in bacteria with single attTn sites: example Pseudomonas aeruginosa [ J)]The P.aeruginosa PAO1 (O5) -LUX was constructed using the PTN 7 transposon system as described in Nature Protocols,2006,1 (1): 153-161). The inhibitory activity of the candidate antibody was determined by detecting the luminescent signal value of P.aeruginosa. A549 cells (human adenocarcinoma alveolar basal epithelial cell line) were inoculated into a white 96-well plate (Nunclon Delta) with DMEM medium containing 10% fbs, and anti-Psl antibody was added to the above cells fused into a monolayer. At a multiplicity of infection of 10 (MOI=10), P.aeruginosa PAO1 (O5) -LUX in logarithmic growth phase was added at 37deg.C with 5% CO 2 Incubate for 1 hour. A549 cells were then washed to remove unbound bacteria, followed by addition of 2YT medium. After a short incubation at 37℃bacteria were quantified and Cam-003 and Wapr-001 were used as control antibodies. The luminous intensity value of the whole board is read in the self-luminous module. The inhibition ratio of the anti-Psl antibody was calculated by setting the value obtained by measurement with the addition of a saturated dose (300. Mu.g/ml) of the control antibody Cam-003 to 100% inhibition and the value obtained by measurement without addition of the anti-Psl antibody to 0% inhibition. The IC50 values of the antibodies were calculated using GraphPad Prism 6, four-parameter method.
The results are shown in FIGS. 1A-1B and Table 9, all of the anti-Psl antibodies showed significantly better effects in blocking the adsorption of P.aeruginosa to A549 than the control antibody Wapr-001; all anti-Psl antibodies showed significantly better or comparable effects in blocking the adsorption of pseudomonas aeruginosa to a549 than the control antibody Cam-003.
TABLE 9 efficacy of anti-Psl antibodies in blocking adsorption of Pseudomonas aeruginosa strains with A549
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Evaluation of anti-Psl antibodies to promote OPK against Pseudomonas aeruginosa
This experiment shows that the anti-Psl lead antibody mediates opsonophagocytic killing (OPK) against pseudomonas aeruginosa. P. aeruginosa PAO1 (O5) -LUX was constructed using the PTN 7 transposon system. The activity of the anti-Psl antibody was determined by detecting the luminescent signal value of P.aeruginosa. The method of OPK detection is as described in (diggiandomico, a., et al, infectImmun 72,7012-7021 (2004)). Briefly, the assays were performed in 96-well plates, with rabbit serum (CREATIVE DIAGNOSTICS, cat#dag136) as a complement source, using differentiated HL-60 cells, p.aeruginosa PAO1 (O5) -LUX in the logarithmic growth phase, and serial dilutions of anti-Psl antibodies. In particular, HL-60 cells are differentiated into human polymorphonuclear leukocytes (PMNs) using methods known in the art (Fleck R A, et al. Use of HL-60Cell Line To Measure Opsonic Capacity of Pneumococcal Antibodies[J ].Clinical&Diagnostic Laboratory Immunology,2005,12 (1): 19). The 96-well plate was coated with PMNs, and 2ml of rabbit serum was diluted with the same volume of medium and added to the 96-well plate at 25 μl/well. anti-Psl antibody was diluted 3-fold in proportion and added to the plate at 10. Mu.l/well. Pseudomonas aeruginosa PAO1 (O5) -LUX in the logarithmic phase was then added at a multiplicity of infection of 0.1 (MOI=0.1). At 37℃with 5% CO 2 After incubation for 4 hours, bacteria were quantified by reading the luminescence intensity values. Cam-003 and Wapr-001 were used as control antibodies. The relative killing rate of the anti-Psl antibody was calculated by setting the value measured by adding a saturated dose (300. Mu.g/ml) of the control antibody Cam-003 to 100% OPK and the value measured by not adding the anti-Psl antibody to 0% OPK. IC50 values of antibodies were calculated using GraphPad Prism 6, four parameter method.
The results are shown in FIGS. 1C-1D and Table 10, all anti-Psl antibodies showed significantly better efficacy in promoting OPK against P.aeruginosa than the control antibody Wapr-001; all anti-Psl antibodies showed better or comparable effects in promoting OPK against pseudomonas aeruginosa than the control antibody Cam-003.
Table 10 anti-Psl antibodies promote OPK efficacy against Pseudomonas aeruginosa
Example 3: full length anti-Psl antibodies broadly neutralize pseudomonas aeruginosa strains
To examine whether anti-Psl antibodies have broad-spectrum neutralizing activity against pseudomonas aeruginosa strains, the ability of anti-Psl antibodies to inhibit adsorption of other clinically relevant pseudomonas aeruginosa strains (e.g., pseudomonas aeruginosa strains of type O1, O6, O16, or O2) to a549 cells, as well as to promote OPK against other clinically relevant pseudomonas aeruginosa strains (e.g., pseudomonas aeruginosa strains of type O1, O6, O16, or O2) was evaluated.
anti-Psl antibodies inhibit adsorption of a549 cells by different pseudomonas aeruginosa strains
The anti-Psl monoclonal antibodies P59, 7H9, 3F12, 2A2 and 6G7 were analyzed for their ability to inhibit the adsorption of A549 cells by different strains of P.aeruginosa (strains O1-52/66 (CNCTC 52/66), O6-57/66 (CNCTC 57/66), O16-177/81 (CNCTC 177/81) and O2-53/66 (CNCTC 53/66)). P. aeruginosa 52/66 (O1) -LUX, 57/66 (O6) -LUX, 177/81 (O16) -LUX and 53/66 (O2) -LUX, A549 cell adsorption inhibition assays were constructed using the PTN 7 transposon system as described in (Choi K H, et al mini-Tn7insertion in bacteria with single attTn sites: example Pseudomonas aeruginosa [ J ]. Nature Protocols,2006,1 (1): 153-161) as described in example 2.
As shown in FIGS. 2A-2D and Table 11, the anti-Psl monoclonal antibodies P59, 7H9, 3F12, 2A2 and 6G7 showed excellent effects in inhibiting adsorption of P.aeruginosa strains (O1-52/66 (FIG. 2A), O6-57/66 (FIG. 2B), O16-177/81 (FIG. 2C) or O2-53/66 (FIG. 2D)) to A549 cells.
TABLE 11 efficacy of anti-Psl antibodies in inhibiting adsorption of A549 cells by different Pseudomonas aeruginosa strains
anti-Psl antibodies promote OPK against different pseudomonas aeruginosa strains
The ability of anti-Psl monoclonal antibodies P59, 7H9 and 3F12 to promote OPK against different Pseudomonas aeruginosa strains (strains O6-57/66, O16-177/81, O1-52/66 and O2-53/66) was analyzed in comparison to the control antibody Psl 0096. P. aeruginosa 57/66 (O6) -LUX, 177/81 (O16) -LUX, 52/66 (O1) -LUX and 53/66 (O2) -LUX were constructed using the PTN 7 transposon system and OPK promotion assays were as described in example 2.
As shown in FIGS. 3A-3D and Table 12, the anti-Psl monoclonal antibodies P59, 7H9 and 3F12 showed comparable or better effects in promoting OPK against Pseudomonas aeruginosa strains (O6-57/66 (FIG. 3A), O16-177/81 (FIG. 3B), O1-52/66 (FIG. 3C) or O2-53/66 (FIG. 3D)) than the control antibody Psl 0096.
Table 12 efficacy of anti-Psl antibodies to promote OPK in different Pseudomonas aeruginosa strains
Example 4: identification of biologically active variants of full-length anti-Psl antibodies
To reduce isomerization and deamidation of antibodies, a set of antibodies in V were constructed H And V L Variants of the full length anti-Psl antibody 7H9, P59 or 3F12, comprising single or combined mutations in the domains, were purified by methods known in the art and their biological activity was assessed by the a549 adsorption blocking assay and OPK promotion assay as described in example 2. Cam-003 served as the control antibody. The IC50 values of the variants inhibiting the adsorption of P.aeruginosa PAO1 (O5) to A549 cells and the EC50 values promoting OPK against P.aeruginosa PAO1 (O5) are shown in tables 13-18, indicating that all candidate antibody variants with mutations described herein exhibited comparable or better function than the control antibody Cam-003. Exemplary heavy and light chain variable domain sequence numbers for anti-Psl antibody variants are shown in table 6.
TABLE 13 efficacy of anti-Psl antibody 7H9 variants in blocking adsorption of Pseudomonas aeruginosa to A549 cells
TABLE 14 efficacy of anti-Psl antibody 7H9 variants to promote OPK against Pseudomonas aeruginosa
Antibody variants OPK(EC50μg/ml) Antibody variants OPK(EC50μg/ml)
Cam-003 0.3753 7H9-m10 0.0512
7H9 0.0926 7H9-m15 0.0490
7H9-m01 0.0869 7H9-m16 0.0650
7H9-m02 0.0758 7H9-m17 0.0410
7H9-m03 0.0536 7H9-m18 0.0266
7H9-m05 0.0420 7H9-m23 0.0284
7H9-m07 0.0662 7H9-m24 0.0846
7H9-m08 0.0383 7H9-m25 0.0812
7H9-m09 0.0534 7H9-m26 0.0491
TABLE 15 efficacy of anti-Psl antibody P59 variants in blocking adsorption of Pseudomonas aeruginosa to A549 cells
Antibody variants ATT(IC50μg/ml) Antibody variants ATT(IC50μg/ml)
Cam-003 3.39 P59-m17 1.53
P59 2.29 P59-m18 1.85
P59-m01 3.48 P59-m19 2.47
P59-m02 2.51 P59-m20 2.21
P59-m03 2.85 P59-m21 2.52
P59-m04 2.32 P59-m22 4.61
P59-m05 1.80 P59-m23 2.53
P59-m06 2.57 P59-m24 2.66
P59-m07 1.60 P59-m25 2.01
P59-m08 2.02 P59-m26 3.49
P59-m09 2.02 P59-m27 2.67
P59-m10 2.26 P59-m28 2.22
P59-m11 2.16 P59-m29 3.11
P59-m12 3.09 P59-m30 2.21
P59-m13 3.43 P59-m31 3.19
P59-m14 3.33 P59-m32 2.76
P59-m15 2.93 P59-m33 2.75
P59-m16 2.14
TABLE 16 efficacy of anti-Psl antibody P59 variants to promote OPK against Pseudomonas aeruginosa
Antibody variants OPK(EC50μg/ml) Antibody variants OPK(EC50μg/ml)
Cam-003 0.3753 P59-m15 0.0649
P59 0.1127 P59-m16 0.0530
P59-m03 0.0542 P59-m17 0.1110
P59-m04 0.0503 P59-m18 0.1063
P59-m05 0.0454 P59-m21 0.0839
P59-m07 0.1151 P59-m22 0.1062
P59-m13 0.1319 P59-m23 0.2215
TABLE 17 efficacy of anti-Psl antibody 3F12 variants in blocking adsorption of Pseudomonas aeruginosa to A549 cells
Antibody variants ATT(IC50μg/ml)
Cam-003 3.39
3F12 2.12
3F12-m01 1.279
TABLE 18 efficacy of anti-Psl antibody 3F12 variants to promote OPK against Pseudomonas aeruginosa
Antibody variants OPK(EC50μg/ml)
Cam-003 0.3753
3F12 0.1258
3F12-m01 0.1233
anti-Psl antibody variants broadly neutralize pseudomonas aeruginosa strains
To examine whether these variants have broad-spectrum neutralizing activity against pseudomonas aeruginosa strains, the variants were evaluated for their ability to block the adsorption of pseudomonas aeruginosa to a549 cells, as well as their ability to promote OPK activity against other clinically relevant pseudomonas aeruginosa strains, e.g., pseudomonas aeruginosa strains of O1, O6, O16, or O2.
anti-Psl antibody variants block adsorption of a549 cells by different pseudomonas aeruginosa strains
Variants P59-m21 and 7H9-m23 of the anti-Psl antibodies were further analyzed for their ability to block the adsorption of different Pseudomonas aeruginosa strains (strains O1-52/66, O2-53/66, O6-57/66 and O16-177/81) to A549 cells. P. aeruginosa 52/66 (O1) -LUX, 53/66 (O2) -LUX, 57/66 (O6) -LUX and 177/81 (O16) -LUX were constructed using the PTN 7 transposon system and the A549 cell adsorption inhibition assay was as described in example 2.
As shown in FIGS. 4A-4D and Table 19, variants P59-m21 and 7H9-m23 of the anti-Psl antibodies exhibited good effects in blocking adsorption of A549 cells by different Pseudomonas aeruginosa strains (O1-52/66 (FIG. 4A), O2-53/66 (FIG. 4B), O6-57/66 (FIG. 4C) or O16-177/81 (FIG. 4D)).
Table 19 efficacy of anti-Psl antibody variants to block adsorption of a549 cells by different pseudomonas aeruginosa strains
anti-Psl antibody variants promote OPK against different pseudomonas aeruginosa strains
The ability of anti-Psl antibody variants P59-m21 and 7H9-m23 to promote OPK against different Pseudomonas aeruginosa strains (O1-52/66, O16-177/81, O6-57/66 or O2-53/66) was analyzed and compared to the control antibody Psl 0096. P. aeruginosa 52/66 (O1) -LUX, 177/81 (O16) -LUX, 57/66 (O6) -LUX and 53/66 (O2) -LUX were constructed using the PTN 7 transposon system and OPK promotion assays were as described in example 2.
As shown in FIGS. 5A-5D and Table 20, variants P59-m21 and 7H9-m23 of the anti-Psl antibodies showed comparable or better effects in promoting OPK against Pseudomonas aeruginosa strains (O1-52/66 (FIG. 5A), O16-177/81 (FIG. 5B), O6-57/66 (FIG. 5C) or O2-53/66 (FIG. 5D)) than the control antibody Psl 0096.
Table 20 efficacy of anti-Psl antibody variants to promote OPK in different Pseudomonas aeruginosa strains
Example 5: characterization of binding specificity of anti-Psl antibodies
Binding affinity of anti-Psl antibody variants
The binding kinetics and affinity of anti-Psl antibody mutants 3F12-m01, 7H9-m23, P59-m21 and the control antibody Psl0096 to Psl were examined by biofilm layer interference (Bio-layer interferometry, BLI) and the results are shown in Table 21.
TABLE 21 binding affinity of anti-Psl antibody variants to Psl
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Binding to recombinant Pseudomonas aeruginosa strain WFPA801 or WFPA800
The binding specificity of anti-Psl antibodies and control antibodies, psl0096, to strain WFPA801 or WFPA800 was detected by ELISA according to the methods previously described (see Ma, l., et al,2006,J Bacteriol 188:8213-8221). Briefly, the present study used Pseudomonas aeruginosa PAO1 mutant WFPA800 (Δpsl) deleted of the Psl promoter or strain WFPA801 (p) that inducible expressed Psl BAD Psl). ELISA plates were coated with strain WFPA801 or WFPA800 and incubated overnight at 4 ℃. After blocking, serial dilutions of antibody were added and incubated for 1 hour at 37 ℃. After washing, alkaline phosphatase-labeled anti-human IgG antibodies (goat anti-human IgG (whole molecule) -HRP, sigma, a 8667) were added and incubated at 37 ℃ for 1 hour. PNPP was added to each well for color development. The reaction was quenched with 3M NaOH. The signal was read at 410nm with a microplate reader.
As shown in FIGS. 6A-6B and Table 22, the binding levels of anti-Psl antibodies 3F12, 7H9-m23, P59-m21 and control antibodies Psl0096 were lower with WFPA800 strain (FIG. 6A). In contrast, all the test antibodies showed high levels of specific binding to WFPA801 (fig. 6B) strain.
TABLE 22 efficacy of anti-Psl antibodies cross-reacting with WFPA801
Antibodies to 3F12 7H9-m23 P59-m21 psl0096
EC50(μg/mL) 0.167 0.203 0.070 0.183
Nonspecific binding of anti-Psl antibodies
The non-specific binding of anti-Psl antibodies 3F12, 7H9-m23 and P59-m21 was further characterized, as compared to the control antibody Psl 0096.
Cross-reactivity with BV particles: according to the method described previously (seeI, et al,2012,mAbs 4:6,753-760), cross-reactivity of anti-Psl antibodies, control antibodies, psl0096, with BV particles was detected by ELISA. Lenzilumab was used as positive control and Tildrakizumab was used as negative control. BV score is the ratio between the OD value measured with the addition of the antibody to be tested and the OD value measured without the addition of the antibody.
The results are shown in fig. 7 and table 23, positive controls showed high levels of binding to BV particles. In contrast, antibodies 3F12, 7H9-m23 or P59-m21 showed very low levels of binding to BV particles, which were lower than or comparable to the control antibody psl0096, similar to the negative control.
TABLE 23 efficacy of anti-Psl antibodies in cross-reacting with BV particles
Antibodies to 3F12 7H9-m23 P59-m21 psl0096 Lenzilumab Tildrakizumab
BV ELISA score 1.1 1.5 1.1 2.1 18.4 1.0
Taken together, these results indicate that the anti-Psl antibodies 3F12, 7H9-m23 and P59-m21 have non-specific binding comparable to or lower than the control antibody Psl 0096.
Example 6: anti-Psl antibodies inhibit biofilm formation by pseudomonas aeruginosa PAO1 (O5) strains
Pseudomonas aeruginosa is the most common model organism for studying biofilm formation, as it has long been associated with biofilm formation in chronic cystic fibrosis lung infections. Biofilm formation is an important mechanism leading to chronic infection colonization and antibiotic resistance. The Psl polysaccharide is an important component of the formation of biofilms by pseudomonas aeruginosa, and an effective anti-Psl antibody should theoretically have the function of inhibiting biofilm formation.The ability of anti-Psl antibodies 3F12, P59-m21, 7H9-m23 and control antibody Psl0096 to inhibit P.aeruginosa biofilm formation was demonstrated in the following experiments, in which HIV neutralizing antibody 10E8 (Huang J, et al, broad and potent neutralization of HIV-1by a gp41-specific human anti-ibody. Nature.2012Nov 15;491 (7424): 406-12) was designated herein as negative control. Briefly, pseudomonas aeruginosa colonies were picked into liquid medium and incubated overnight at 37 ℃. The OD600 value of the culture medium containing the pseudomonas aeruginosa was adjusted to 1.0 and diluted 10 6 100 μl of diluted Pseudomonas aeruginosa and anti-Psl antibodies were added to 96-well plates and incubated at 30deg.C for 24 hours. Subsequently, the medium was gently removed, and the culture plate was washed 3 times with sterile water, thereby removing bacteria that did not form a biofilm. Mu.l of 1% crystal violet was added to each well and incubated for 20 minutes for staining. The plates were rinsed 3 times with sterile water, 150. Mu.l of 33% acetic acid was added, and the incubation was performed for 20 minutes to extract crystal violet. Acetic acid containing crystal violet was transferred to another well and OD was read at 490 nm. The percentage of biofilm formation was calculated by setting the OD490 value obtained by the measurement without the addition of the anti-Psl antibody to 100% biofilm formation and the OD490 value obtained by the measurement without the addition of P.aeruginosa to 0% biofilm formation.
As shown in fig. 8, all anti-Psl antibodies tested significantly inhibited biofilm formation (P < 0.05) over a dose range of 300-900 μg/ml compared to the negative control. In particular, the anti-Psl antibodies 3F12, 7H9-m23 and P59-m21 have better or comparable biofilm formation inhibiting effects than the control antibody Psl 0096.
Example 7: animal survival rate of a mouse model of pseudomonas aeruginosa bacteremia using anti-Psl antibodies
The ability of anti-Psl antibodies to increase survival in a bacteremia mouse model was assessed. HIV-10E8 served as a negative control. A mouse bacteremia model was constructed by intraperitoneal infection using the method described previously (see Warrener et al, 2014,Antimicrob.Agents Chemother, 58, 4384-4391).
Higher doses of anti-Psl antibodies improve survival in bacteremia model mice
The ability of anti-Psl antibody P59 (15 mg/kg in mouse body weight) to increase mouse survival in bacteremia models was evaluated compared to control antibody Cam-003. HIV-10E8 served as a negative control.
To establish a mouse bacteremia model, 7-8 week old BALB/c mice (Vetolihua) were randomly grouped into 8-10 groups. Antibodies were intraperitoneally injected (i.p.) 24 hours prior to infection at a dose of 15mg/kg based on the weight of the mice. Mice were vaccinated intraperitoneally with 2-fold lethal doses (2×ld90=5×10) 5 CFU) pseudomonas aeruginosa (O6-57/66 strain) which represents a highly cytotoxic pseudomonas aeruginosa serotype associated with clinical disease. Mice survival was recorded within 5 days after infection.
As a result, as shown in FIG. 9A, in the bacteremia model with a 2-fold lethal dose (2 XLD 90) inoculated with Pseudomonas aeruginosa (57/66), the protection by the anti-Psl antibody P59 was significantly better than that of the control antibody Cam-003 (P < 0.05) at the same antibody dose. The differences in survival were calculated using a log rank test.
Lower doses of anti-Psl antibodies improve survival in bacteremia model mice
The ability of anti-Psl antibodies P59, 1D10, 7H9, 2A2 and 6G7 (at lower doses of 10mg/kg, based on mouse body weight) to increase mouse survival in bacteremia models was evaluated compared to control antibody Cam-003. HIV-10E8 served as a negative control.
BALB/c mice (Vetolihua) 7-8 weeks old were randomly grouped, with 8-10 mice per group. The antibodies were intraperitoneally injected (i.p.) 24 hours prior to infection at a dose of 10mg/kg based on the weight of the mice. Mice were vaccinated intraperitoneally with 3-fold lethal doses (3×ld90=7×10) 5 CFU) Pseudomonas aeruginosa (O6-57/66 strain). Mice survival was recorded within 6 days after infection.
Results As shown in FIG. 9B, in the bacteremia model with a 3-fold lethal dose (3 XLD 90) inoculated with Pseudomonas aeruginosa (57/66), all anti-Psl antibodies showed significantly better survival-improving effect than the negative control HIV-10E8 at lower doses (10 mg/kg, based on mouse body weight). The anti-Psl antibodies 7H9 and 6G7 exhibited significantly better survival-improving effects (P < 0.05) than the control antibody Cam-003, while the anti-Psl antibodies P59, 1D10 and 2A2 exhibited comparable or better survival-improving effects than the control antibody Cam-003. The differences in survival were calculated using a log rank test.
Lower doses of anti-Psl antibodies improve survival of mice vaccinated with higher amounts of bacteremia model with pseudomonas aeruginosa
anti-Psl antibodies 3F12 and 7H9 (at lower doses of 10mg/kg, based on mouse body weight) were evaluated for their ability to increase mouse survival in bacteremia models vaccinated with higher amounts (4×ld90) of pseudomonas aeruginosa, as compared to control antibody Psl 0096. HIV-10E8 was used as a negative control.
BALB/c mice (Vetolihua) 7-8 weeks old were randomly grouped, with 8-10 mice per group. The antibodies were intraperitoneally injected (i.p.) 24 hours prior to infection at a dose of 10mg/kg based on the weight of the mice. Mice were vaccinated intraperitoneally with 4-fold lethal doses (4×ld90=7×10) 5 CFU) Pseudomonas aeruginosa (O6-57/66 strain). Mice survival was recorded within 6 days after infection.
As a result, as shown in FIG. 9C, in the bacteremia model with a 4-fold lethal dose (4 XLD 90) inoculated with Pseudomonas aeruginosa (57/66), the amount of the compound to be administered was lower (10 mg/kg based on the weight of the mouse). anti-Psl antibodies 3F12 and 7H9 exhibited significantly better survival-improving effects (P < 0.05) than the control antibody Psl 0096. The differences in survival were calculated using a log rank test.
anti-Psl antibody variants improve survival in bacteremia model mice
Evaluation of anti-Psl antibody variants 7H9-m23, 7H9-m24,7H9-m25, 3F12-m01 and P59-m21 (with lower doses of 10mg/kg, based on mouse weight) at higher levels of P.aeruginosa inoculation (4 XLd90=9×10) 5 CFU) ability to increase survival in mice in bacteremia models. HIV-10E8 served as a negative control.
BALB/c mice (Vetolihua) 7-8 weeks old were randomly grouped, with 8-10 mice per group. The anti-Psl antibody variant was intraperitoneally injected (i.p.) 24 hours prior to infection at a dose of 10mg/kg based on the weight of the mice. Mice were vaccinated intraperitoneally with 4-fold lethal doses (4×ld90=9×10) 5 CFU) Pseudomonas aeruginosa (O6-57/66 strain). Mice survival was recorded within 6 days after infection.
Results As shown in FIG. 9D, all anti-Psl antibody variants (7H 9-m23, 7H9-m24,7H9-m25, 3F12-m01 and P59-m 21) showed significantly better survival-improving effects (P < 0.05) than the negative control HIV-10E8 at lower doses of administration (10 mg/kg, based on mouse body weight) in the bacteremia model with a 4-fold lethal dose (4 XLD 90) of P.aeruginosa (57/66) inoculation. The differences in survival were calculated using a log rank test.
Example 8: anti-Psl antibody variants reduce organ load in acute pneumonia model mice
anti-Psl antibody variants 3F12-m01, 7H9-m24 and P59-m21 (with lower dosing amounts of 10mg/kg, based on mouse body weight) were evaluated for their ability to reduce organ load in the mouse acute lung inflammation model. HIV-10E8 was used as a negative control.
BALB/c mice (Venlhua) 7-8 weeks old were intraperitoneally injected (i.p.) with antibody or PBS 24 hours before infection at a dose of 15mg/kg based on the weight of the mice. To induce acute pneumonia, mice were vaccinated 5×10 nasal cavity 6 Pseudomonas aeruginosa (strain 57/66) of CFU. 24 hours after infection, mice were sacrificed and lungs, spleen, kidneys were extracted to measure colony forming units (expressed as CFU), which represent the load of pseudomonas aeruginosa in individual organ samples.
The results are shown in FIG. 10, all anti-Psl antibody variants 3F12-m01, 7H9-m24 and P59-m21 exhibited higher efficacy (P < 0.05) in reducing organ load in lung, spleen, kidney of the pneumonia model mice compared to negative control HIV-10E 8.
Example 9: combination of anti-Psl antibodies and antibiotics for treatment of pseudomonas aeruginosa infection
anti-Psl antibody combined with antibiotics to improve survival rate of mice abdominal cavity infection model
The ability of anti-Psl antibody 3F12 and 3F12 in combination with antibiotics (meropenem, tobramycin or ciprofloxacin) to increase survival in celiac infected model mice was evaluated. HIV-10E8 served as a negative control.
24 hours before infection to 7-8 weeksThe aged BALB/c mice (Venlhua) were either intraperitoneally injected with antibodies or 2 hours after infection with antibiotics. Specifically, the anti-Psl antibody 3F12 (7 mg/kg), meropenem (8 mg/kg), tobramycin (2 mg/kg), ciprofloxacin (2 mg/kg) were administered to mice, respectively. For the combination treatment, antibody 3F12 (7 mg/kg) was intraperitoneally injected 24h before infection, meropenem (8 mg/kg), tobramycin (2 mg/kg), ciprofloxacin (2 mg/kg) were intraperitoneally injected 2h after infection, respectively. To induce intraperitoneal infection, BALB/c mice were intraperitoneally vaccinated with 3-fold lethal doses (3×ld90=7×10) 5 CFU) Pseudomonas aeruginosa (strain 57/66). Mice survival was recorded within 5 days after infection.
Results As shown in FIG. 11, the use of 3F12 (7 mg/kg) in combination with the antibiotics meropenem (8 mg/kg), tobramycin (2 mg/kg) or ciprofloxacin (2 mg/kg) significantly improved the survival rate (p < 0.05) of mice compared to antibody treatment alone or antibiotic treatment alone in a 3-fold lethal dose (3 XLD 90) of P.aeruginosa (57/66 strain) in a peritoneal infection model. These results demonstrate the clinical potential of the anti-Psl antibodies described herein in combination with antibiotics in neutralizing pseudomonas aeruginosa.
Example 10: pharmacokinetics of anti-Psl antibodies and variants
To study the in vivo pharmacokinetics of the anti-Psl antibodies 3F12, variants 7H9-m23 and P59-m21, the levels of 3F12, 7H9-m23, P59-m21 and the control antibody Psl0096 in rat plasma were measured over time, in comparison to the control antibody.
Pharmacokinetics in rats: 20 healthy adult rats (weighing about 0.2 kg) of similar weight were intravenously injected with 3mg/kg of 3F12, 7H9-m23, P59-m2 or psl0096, respectively. Blood samples were collected 1 hour after injection and then 0 hour, 0.5 hour, 2 hours, 8 hours, 1 day, 3 days, 7 days, 11 days, 17 days, 23 days, 31 days, 41 days, 52 days after injection. After centrifugation, the concentration of antibodies in the plasma was determined by ELISA. In ELISA experiments, 96-well plates were coated with Psl polysaccharide. The following day, after PBST washing, the plates were blocked with 200. Mu.L of PBS-milk for 1 hour, and after PBST washing, plasma was added to the plates and incubated for 1 hour at 37 ℃. 96-well plates were washed 6 times with 0.1% TBST, then 100. Mu.L goat anti-human Fc antibody AP (diluted 1:3000 in PBS) was added to each well and incubated for 1 hour. After 6 washes with 0.1% TBST, 50. Mu.l of pNPP was added to each well and developed for 10-20min at 37℃using antibody-linked alkaline phosphatase, yielding a colorimetric signal. Colorimetric signals were read with a microplate reader at a wavelength of 410 nm.
The results are shown in FIG. 12, where the half-lives of 3F12, 7H9-m23 and P59-m21 were comparable to the control antibody, psl0096, at the intravenous dose tested (3 mg/kg), indicating that the anti-Psl antibodies and variants exhibited stable pharmacokinetics comparable to the control antibody, psl0096, in rats.

Claims (17)

1. An isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl, comprising:
(i)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(ii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 165; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(iii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO. 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO. 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO. 166; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(iv)V H the V is H Comprising: HC-CDR1, amino acid sequence thereof4 of SEQ ID NO, 16 of HC-CDR2, 35 of HC-CDR 3; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(v)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 167; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(vi)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 168; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 65;
(vii)V H The V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 199;
(viii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 200;
(ix)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO. 4, the amino acid sequence of which is SEQ ID NO. 16, and the amino acid sequence of which is HC-CDR3, the amino acid sequence of which is SEQ ID NO. 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 76;
(x)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 201;
(xi)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 202;
(xii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 78;
(xiii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 203;
(xiv)V H The V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 204;
(xv)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, whose amino acid sequence is SEQ ID NO. 40, LC-CDR2, whose amino acid sequence is SEQ ID NO. 54, and LC-CDR3, whose amino acid sequence is SEQ ID NO. 205;
(xvi)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, whose amino acid sequence is SEQ ID NO. 40, LC-CDR2, whose amino acid sequence is SEQ ID NO. 54, and LC-CDR3, whose amino acid sequence is SEQ ID NO. 206;
(xvii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 207;
(xviii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, whose amino acid sequence is SEQ ID NO. 40, LC-CDR2, whose amino acid sequence is SEQ ID NO. 54, and LC-CDR3, whose amino acid sequence is SEQ ID NO. 208;
(xix)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 77;
(xx)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 209;
(xxi)V H The V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 210;
(xxii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 211;
(xxiii)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 27; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 212;
(xxiv)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 35; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 76;
(xxv)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 35; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 77;
(xxvi)V H the V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 35; v (V) L The V is L Comprising: LC-CDR1, the amino acid sequence of which is SEQ ID NO. 40, LC-CDR2, the amino acid sequence of which is SEQ ID NO. 54, and LC-CDR3, the amino acid sequence of which is SEQ ID NO. 78; or alternatively
(xxvii)V H The V is H Comprising: HC-CDR1, the amino acid sequence of which is SEQ ID NO 4, HC-CDR2, the amino acid sequence of which is SEQ ID NO 16, and HC-CDR3, the amino acid sequence of which is SEQ ID NO 169; v (V) L The V is L Comprising: LC-CDR1 having the amino acid sequence SEQ ID NO. 40, LC-CDR2 having the amino acid sequence SEQ ID NO. 54, and LC-CDR3 having the amino acid sequence SEQ ID NO. 65.
2. An isolated antibody or antigen-binding fragment according to claim 1 that specifically binds pseudomonas Psl, comprising:
(i)V H the V is H Comprising the amino acid sequence SEQ ID NO. 82, or a variant having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 82A body sequence; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 94 or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 94;
(ii)V H the V is H Comprising any one of the amino acid sequences of SEQ ID NOs 105-110, or comprising a variant sequence having at least 90% sequence homology with any one of the amino acid sequences of SEQ ID NOs 105-110;
v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 94 or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 94;
(iii)V H the V is H Comprising the amino acid sequence SEQ ID NO. 82, or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 82; v (V) L The V is L Comprising any one of the amino acid sequences of SEQ ID NOs 111-127, or comprising a variant sequence having at least 90% sequence homology with any one of the amino acid sequences of SEQ ID NOs 111-127;
(iv)V H the V is H Comprising the amino acid sequence SEQ ID NO. 107 or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 113, or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 113;
(v)V H the V is H Comprising the amino acid sequence SEQ ID NO. 107 or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 123, or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 123; or alternatively
(vi)V H The V is H Comprising the amino acid sequence SEQ ID NO. 107 or comprising a variant sequence having at least 90% sequence homology with the amino acid sequence SEQ ID NO. 107; v (V) L The V is L Comprising the amino acid sequence SEQ ID NO. 116, or comprising the amino acid sequence SEQ IDNO. 116 variant sequences having at least 90% sequence homology.
3. The isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to claim 1 or 2, wherein the antibody or antigen-binding fragment comprises an Fc fragment.
4. An isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to claim 3, wherein the antibody or antigen-binding fragment is a full length IgG antibody.
5. The isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to claim 4, wherein the antibody or antigen-binding fragment is a full length IgG1 or IgG4 antibody.
6. An isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to claim 1 or 2, wherein the antibody or antigen-binding fragment is chimeric, fully human or humanized.
7. The isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to claim 1 or 2, wherein the antibody or antigen-binding fragment is selected from the group consisting of Fab, fab ', F (ab) '2, fab ' -SH, single chain antibody (scFv), fv fragment, dAb, fd, or diabody.
8. An isolated nucleic acid molecule encoding the isolated antibody or antigen-binding fragment of any one of claims 1-7 that specifically binds pseudomonas Psl.
9. A vector comprising the nucleic acid molecule of claim 8.
10. An isolated host cell comprising the antibody or antigen-binding fragment of any one of claims 1-7, the nucleic acid molecule of claim 8, or the vector of claim 9.
11. A method of making an isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl, comprising:
a) Culturing the host cell of claim 10 under conditions effective to express an anti-Psl antibody or antigen-binding fragment; and is also provided with
b) Obtaining an expressed anti-Psl antibody or antigen-binding fragment in a host cell.
12. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment of any one of claims 1-7 that specifically binds pseudomonas Psl, the nucleic acid molecule of claim 8, the vector of claim 9, or the isolated host cell of claim 10, and a pharmaceutically acceptable carrier.
13. Use of an isolated antibody or antigen-binding fragment that specifically binds pseudomonas Psl according to any one of claims 1-7, a nucleic acid molecule according to claim 8, a vector according to claim 9, an isolated host cell according to claim 10, or a pharmaceutical composition according to claim 12 for the manufacture of a medicament for the treatment of pseudomonas aeruginosa infection or for the treatment of one or more symptoms caused by pseudomonas aeruginosa infection.
14. The use of claim 13, wherein the symptoms include one or more of fever, chills, fatigue, muscle and joint pain, joint swelling, headache, diarrhea, rash, wound pus, bacteremia, acute pneumonia, intraperitoneal infection, respiratory tract infection, septic shock, suppurative arthritis, enteritis, skin and soft tissue infection, urinary tract infection, intestinal tract infection, ulcerative keratitis, chronic suppurative otitis media, mastoiditis, sinusitis, or endocarditis.
15. The use of claim 13, wherein the pharmaceutical composition is further administered in combination with one or more therapeutic agents.
16. The use as claimed in claim 15, wherein at least one therapeutic agent is an antibiotic.
17. The use as claimed in claim 16, wherein the antibiotic is one or more of imipenem, tobramycin, ciprofloxacin, meropenem or a Qu Nazhong.
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